Process for the solid phase synthesis of aldehyde, ketone, oxime, amine, hydroxamic acid and αβ-unsaturated carboxylic acid and aldehyde compounds

ABSTRACT

This invention is directed to a process for the solid phase synthesis of aldehyde, ketone, oxime, amine, hydroxamic acid and α,β-unsaturated carboxylic acid and aldehyde compounds and to polymeric hydroxylamine resin compounds useful therefor.

CROSS REFERENCE TO RELATED APPLICATIONS

This invention is a continuation-in-part of International PatentApplication No. PCT/US97/23920, filed Dec. 17, 1997, which claimsbenefit of U.S. patent application Ser. No. 60/032,453, filed Dec. 19,1996, and U.S. patent application Ser. No. 60/033,881, filed Dec. 24,1996; and a continuation in part of U.S. patent application Ser. No.08/928,943, filed Sep. 12, 1997, which in turn is a continuation ofInternational Patent Application No. PCT/US97/00264, filed Jan. 2, 1997.

FIELD OF THE INVENTION

This invention is directed processes for the solid-phase synthesis ofaldehyde, ketone, oxime, amine, and hydroxamic acid and α,β-unsaturatedcarboxylic acid and aldehyde compounds and to polymeric hydroxylamineresin compounds useful therefor.

BACKGROUND OF THE INVENTION

Solid-phase synthetic techniques, in which a reagent is immobilized on apolymeric material which is inert to the reagents and reactionconditions employed, as well as being insoluble in the media used, areimportant tools for preparing amides, peptides and hydroxamic acids. Forsolid phase peptide synthesis, a summary of the many techniques may befound in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis,2nd. Ed., Pierce Chemical Co. (Chicago, Ill., 1984); J. Meienhofer,Hormonal Proteins and Peptides, vol. 2, p. 46, Academic Press (NewYork), 1973; and E. Atherton and R. C. Sheppard, Solid Phase PeptideSynthesis: A Practical Approach, IRL Press at Oxford University Press(Oxford, 1989). For the use of solid phase methodology in thepreparation of non-peptide molecules see Leznoff, C. C., Acc. Chem.Res., 11, 327-333 (1978).

A number of polymeric reagents have found synthetic use in simplefunctional group transformations. See A. Akelalh and D. C. Sherrington,Application of Functionalized Polymers in Organic Synthesis, Chem Rev.,81, 557-587 (1981) and W. T. Ford and E. C. Blossey, Polymer SupportedReagents, Polymer supported Catalysts, and Polymer Supported CouplingReactions, in Preparative Chemistry using Supported Reagents, PierreLaszlo, ed., Academic Press, Inc., 193-212 (1987). For the use ofpolymeric reagents in oxidation reactions see J. M. J. Frechet et al.,J. Org. Chem., 43, 2618 (1978) and G. Cainelli et al., J. Am. Chem.Soc., 98, 6737 (1976). For the use of polymeric reagents in halogenationreactions see J. M. J. Frechet et al., J. Macromol. Sci. Chem., A-11,507 (1977) and D. C. Sherrington et al., Eur. Polym. J., 13, 73, (1977).For the use of polymeric reagents in epoxidation reactions see J. M. J.Frechet et al., Macromolecules, 8, 130 (1975) and C. R. Harrison et al.,J. Chem. Soc. Chem. Commun., 1009 (1974). For the use of polymericreagents in acylation reactions see M. B. Shambhu et al., Tet. Lett.,1627 (1973) and M. B. Shambhu et al., J. Chem. Soc. Chem. Commun., 619(1974). For the use of polymeric reagents in Wittig reactions see S. V.McKinley et al., J. Chem. Soc. Chem. Commun., 134 (1972).

Polymeric reagents have also found widespread use in combinatorialsynthesis and for preparing combinatorial libraries. See F. Balkenhohlet al., Angew. Chem. Int. Ed. Engl., 35, 2288-2337 (1996) and L. A.Thompson et al., Chem Rev., 96, 555-600 (1996).

A polymeric reagent has the advantage of ease of separation from lowmolecular weight reactants or products by filtration or selectiveprecipitation. The polymeric reagent can also be used in excess toeffect fast and quantitative reactions such as in the case ofacylations, or a large excess of reactants may be used to drive theequilibrium of the reaction towards product formation to provideessentially quantitative conversion to product, as see in solid phasepeptide synthesis. A further advantage of supported reagents andcatalysts is the fact that they are recyclable and that they lend easilyto automated processes. In addition, supported analogs of toxic andodorous reagents are safer to use.

PCT application publication no. WO96/26223 discloses the synthesis ofhydroxamic acid compounds using a solid phase hydroxylamine substrate.

Prasad et al. disclose a O-methylhydroxylamine-polystyrene resincompound in J. Steroid Biochem., 18, 257-261 (1983).

Resin-bound Weinreb-like amides are disclosed by Fehrentz et al., Tet.Lett., 1995, 36, 7871-7874 and Dinh et al., Tet. Lett., 1996, 37,1161-1164.

Polymeric Horner-Wadsworth-Emmons reagents are disclosed by Wipf et al.,J. Org. Chem., 1997, 62, 1586 and Johnson et al., Tetrahedron Lett.,1995, 36, 9253.

SUMMARY OF THE INVENTION

This invention is directed to a process for the preparation of a ketonecompound of formula ##STR1## wherein R_(c) and R_(a) are independentlyaliphatic or aromatic, comprising

(a) reacting an N-alkylated polymeric hydroxamic acid resin compound offormula ##STR2## wherein is a solid support, L is absent or a linkinggroup and R_(b) is aliphatic or aryl with an organometallic reagent offormula R_(c) M wherein R_(c) is an aliphatic or aryl anion and M is ametal cation; and

(b) liberating the ketone compound from the resin.

In another aspect, this invention is directed to a process for thepreparation of an aldehyde compound of formula R_(a) CHO wherein R_(a)is defined above, comprising

(a) reacting an N-alkylated polymeric hydroxamic acid resin compound offormula ##STR3## wherein , L and R_(a) and R_(b) are defined above; witha reducing agent; and

(b) liberating the aldehyde compound from the resin.

In another aspect, this invention is directed to a process for thepreparation of a N-alkylated polymeric hydroxamic acid resin compound offormula ##STR4## wherein , L and R_(a) and R_(b) are defined above,comprising (a) coupling a carboxylic acid compound of formula R_(a) CO₂H with a polymeric hydroxylamine resin compound of formula ##STR5## toform a polymeric hydroxamic acid resin compound of formula ##STR6## (b)reacting the polymeric hydroxamic acid resin compound with an alkylatingagent of formula R_(b) LG wherein LG is a leaving group.

In another aspect, this invention is directed to a process for thepreparation of a N-alkylated polymeric hydroxamic acid resin compound offormula ##STR7## wherein , L and R_(a) and R_(b) are defined above,comprising (a) reacting a N-protected polymeric hydroxamic acid resincompound of formula ##STR8## wherein P is an amine protecting group,with an alkylating agent of formula R_(b) LG wherein LG is definedabove, to form a polymeric N-protected N-alkylated hydroxylamine resincompound of formula ##STR9## (b) removing the amine protecting group toform a polymeric N-alkylated hydroxylamine resin compound of formula##STR10## (c) coupling the polymeric N-alkylated hydroxylamine resincompound with a carboxylic acid compound of formula R_(a) CO₂ H.

In another aspect, this invention is directed to a process for preparinga hydroxamic acid compound of formula ##STR11## wherein A² is a directbond, alkylene, or NR¹³ ;

R¹³ is hydrogen or alkyl;

R⁹ is --L¹ --R¹⁴ or --L² --R¹⁵ ;

L¹ is a direct bond or alkylene;

R¹⁴ is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl,cyclocarbamoyl, cycloimidylalkyl, heterocyclyl, heteroaryl,--NH--C(═O)--NH₂, (N-carbamoyl)cyclic amine,--C═N--O--C(═O--C(═O)--C(═O)--NY¹ Y², --NY¹ SO₂ aryl, --NHR¹³, --SR¹³ or--OR¹³ ;

L² is alkenylene or alkynylene;

R¹⁵ is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl,heterocyclylalkyl or heteroaryl;

R¹⁰ and R¹² are independently hydrogen or alkyl; or R¹⁰ and R¹² togetherform a bond, or R¹⁰ and R⁹ taken together with the carbon atom throughwhich R¹⁰ and R⁹ are attached form spirocycloalkyl;

R¹¹ is a group --L³ --R¹⁶, or R¹¹ and R⁹ taken together with the carbonatoms through which R¹¹ and R⁹ are attached form cycloalkylene; or R¹¹and R¹² taken together with the carbon atom through which R¹¹ and R¹²are attached form spirocycloalkyl;

L³ is a direct bond, alkylene, alkenylene or alkynylene;

R¹⁶ is hydrogen, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl,aryl, heteroaryl, fused arylcycloalkyl, fused heteroarylcycloalkyl,fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fusedarylheterocyclyl, fused heteroarylheterocyclyl, fusedarylheterocyclenyl, fused heteroarylheterocyclenyl, fusedcycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fusedheterocyclenylaryl, fused cycloalkylheteroaryl, fusedcycloalkenylheteroaryl, fused heterocyclenylheteroaryl, fusedheterocyclylheteroaryl, --NH--C(═O)--NH₂, --C═N--O--C(═O)--NH₂,--C(═O)--NY¹ Y² ; --NY¹ SO₂ aryl, --NR¹³, --SR¹³, or --OR¹³ ;

Y¹ and Y² are independently hydrogen, alkyl, aralkyl, and aryl, or Y¹and Y² taken together with the nitrogen atom to which Y¹ and Y² areattached form azaheterocyclyl;

Ar is selected from the group of formulae ##STR12## R¹⁷ is alkyl, orwhen Z³ is a direct bond then R¹⁷ is hydrogen, alkyl, alkenyl oralkynyl;

R¹⁸ is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl,heteroaryl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fusedarylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl,fused heteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, fused cycloalkenylaryl, fused cycloalkylaryl,fused heterocyclylaryl, fused heterocyclenylaryl, fusedcycloalkylheteroaryl, fused cycloalkenylheteroaryl, fusedheterocyclenylheteroaryl or fused heterocyclylheteroaryl;

R¹⁹ is R²⁰, --OR²⁰, --SR²⁰, --SOR²⁰, --SO₂ R²⁰, --SO₂ NR²⁰ R²¹, --NR²⁰SO₂ R²¹, --NR²⁰ R²¹, --O(C═O)NR²⁰ R²¹, --NR²⁰ C(═O)R²¹, --N(OH)C(═O)R²⁰,or --C(═O)N(OH)R²¹,

R²⁰ and R²¹ are independently hydrogen, alkyl, alkenyl, cycloalkyl,cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, fusedarylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl,fused heteroarylcycloalkenyl, fused arylheterocyclyl, fusedheteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, fused cycloalkenylaryl, fused cycloalkylaryl,fused heterocyclylaryl, fused heterocyclenylaryl, fusedcycloalkylheteroaryl, fused cycloalkenylheteroaryl, fusedheterocyclenylheteroaryl, fused heterocyclylheteroaryl, aralkyl orheteroaralkyl; or R²⁰ and R²¹ taken together with the nitrogen atom towhich R²⁰ and R²¹ are attached form azaheterocyclyl;

A³ is a direct bond, alkylene, alkenylene or alkynylene;

Z¹ and Z³ are independently a direct bond, oxygen, sulfur or NH;

Z² is a direct bond, oxygen or sulfur;

B, C, D, and E are independently are CH or heteroatom selected from O,S, N, NOR²² or NR²², or three of B, C, D or E are independently CH orheteroatom selected from O, S, N or NR²², and the other of B, C, D or Eis a direct bond; and two of B, C, D and E that are in adjacentpositions are other than O or S;

R²² is hydrogen alkyl, aryl, lower aralkyl, heteroaryl or lowerheteroaralkyl

Q¹, Q² and Q³ independently are CH, CX¹ or N;

X¹ is halogen; and

n is 0, 1 or 2; or

a prodrug thereof, acid isostere thereof, pharmaceutically acceptablesalt thereof, or solvate thereof,

comprising treating a polymeric hydroxamic acid resin compound offormula ##STR13## with acid.

In another aspect, this invention is directed to a process for thepreparation of a polymeric oxime ether resin compound of formula##STR14## wherein and L are as defined herein is and R_(d) and R_(e) areindependently H, aliphatic or aromatic, comprising reacting a polymerichydroxylamine resin compound of formula ##STR15## with a carbonylcompound of formula ##STR16##

In another aspect, this invention is directed to a process for thepreparation of an α-amine compound of formula ##STR17## wherein R_(d)and R_(c) are independently H, aliphatic or aryl, provided that R_(d)and R_(c) are not both H, comprising reductively cleaving a polymericoxime ether resin compound of formula ##STR18## wherein and L are asdefined herein.

In another aspect, this invention is directed to a process for thepreparation of a substituted α-amine compound of formula ##STR19##wherein R_(d) and R_(e) are independently H, aliphatic or aromatic,provided that R_(d) and R_(e) are not both H, and R_(f) is aliphatic oraromatic, comprising

(a) reacting a polymeric oxime ether compound of formula ##STR20##wherein and L are as defined herein, with an organometallic reagent offormula R_(f) M wherein Rf is an aliphatic or aromatic anion and M is ametal cation, to form a polymeric α-substituted hydroxylamine resincompound of formula ##STR21## (b) reductively cleaving the a-substitutedhydroxylamine resin compound.

In another aspect, this invention is directed to a process for thepreparation of a lactone compound of formula ##STR22## wherein R_(g),R_(h) and R_(i) are aliphatic or aromatic and Ph is phenyl, comprising

(a) treating an α,β-unsaturated polymeric hydroxamic acid ester resincompound of formula ##STR23## wherein and L are as defined herein, withthiophenol and a radical initiator to form a polymeric oximyl lactonecompound of formula ##STR24## (b) treating the polymeric oximyl lactonecompound with aqueous acid.

In another aspect, this invention is directed to a process for thepreparation of an α,β-unsaturated polymeric hydroxamic acid ester resincompound of formula ##STR25## wherein , L and R_(g) and R_(h) and R_(i)are as defined herein, comprising reacting a polymeric hydroxylamineresin compound of formula ##STR26## with an α,β-unsaturated carboxylicacid ester compound of formula ##STR27##

In another aspect, this invention is directed to a process for thepreparation of an α-cyclic hydroxylamine compound of formula ##STR28##wherein R_(j) and R_(k) are aliphatic or aromatic and Q is --O-- or--CH₂ --, comprising

(a) treating a polymeric acetophenone oxime compound of formula##STR29## wherein and L are as defined herein, with trialkyltin hydrideand a radical initiator to form a polymeric α-cyclic hydroxylamine resincompound of formula ##STR30## (b) treating the polymeric α-cyclichydroxylamine resin compound with aqueous acid.

In another aspect, this invention is directed to a process for thepreparation of a α-cyclic amino compound of formula ##STR31## whereinR_(j) and R_(k) are aliphatic or aromatic and Q is --O-- or --CH₂ --,comprising reductively cleaving a polymeric α-cyclic hydroxylamine resincompound of formula ##STR32## wherein and L are as defined herein.

In another aspect, this invention is directed to a process for thepreparation of a α-cyclic hydroxylamine compound of formula ##STR33##wherein R_(j), R_(k) and R_(l) are aliphatic or aromatic and Q is --O--or --CH₂ --, comprising

(a) treating a polymeric acetophenone oxime compound of formula##STR34## wherein and L are as defined herein, with trialkyltin hydrideand a radical initiator to form a polymeric α-cyclic hydroxylamine resincompound of formula ##STR35## (b) treating the polymeric α-cyclichydroxylamine resin compound with aqueous acid.

In another aspect,, this invention is directed to a process for thepreparation of a α-cyclic amino coin pound of formula ##STR36## whereinR_(j), R_(k) and R_(l) are aliphatic or aromatic and Q is --O-- or --CH₂--, comprising reductively cleaving a polymeric α-cyclic hydroxylamineresin compound of formula ##STR37## wherein and L are as defined herein.

In another aspect, this invention is directed to a N-protectedhydroxylamine resin compound of formula ##STR38## wherein and L are asdefined herein and P is an amine protecting group, provided that P isother than 4-methoxybenzyl or 2,4-dimethoxybenzyl.

In another aspect, this invention is directed to a polymerictetrafluorophenyl hydroxylamine resin compound of formula ##STR39##wherein , A, R³ and R⁴ are as defined herein and P¹ is an amineprotecting group.

In another aspect, this invention is directed to a process for preparinga α,β-unsaturated alkenoate resin compound of formula ##STR40## wherein, and L are as defined herein; R_(m) is H or aliphatic; and R_(n) isaliphatic or aromatic, comprising

(a) treating a mixture in a reaction vessel of a first solvent and apolymeric phosphonoacetoxy resin compound of formula ##STR41## whereinR₂₀ and R₂₀ are alkyl, with excess base; (b) draining the solvent fromthe reaction vessel; and

(c) adding a solution of an aldehyde of formula R_(n) CHO in a lesspolar second solvent.

DETAILED DESCRIPTION OF THE INVENTION

Definitions of Terms

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings.

"Solid support" means a substrate which is inert to the reagents andreaction conditions described herein, as well as being substantiallyinsoluble in the media used. Representative solid supports includeinorganic substrates such as kieselguhr, silica gel, and controlled poreglass; organic polymers including polystyrene, including 1-2%copolystyrene divinyl benzene (gel form) and 20-40% copolystyrenedivinyl benzene (macro porous form), polypropylene, polyethylene glycol,polyacrylamide, cellulose, and the like; and compositeinorganic/polymeric compositions such as polyacrylamide supported withina matrix of kieselguhr particles. See J. M. Stewart and J. D. Young,Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago,Ill., 1984).

In addition, "solid support" includes a solid support as described abovewhich is affixed to a second inert support such as the pins described inTechnical Manual, Multipin™ SPOC, Chiron Technologies (1995) andreferences therein which comprise a detachable polyethylene- orpolyproylene-based head grafted with an amino functionalizedmethacrylate copolymer and an inert stem.

In addition, "solid support" includes polymeric supports such as thepolyethylene glycol supports described by Janda et al., Proc. Natl.Acad. Sci. USA, 92, 6419-6423 (1995) and S. Brenner, WO 95/16918, whichare soluble in many solvents but can be precipitated by the addition ofa precipitating solvent.

"Polymeric hydroxylamine resin compound" means a solid support asdefined above which is chemically modified as is known in the art toincorporate a plurality of hydroxylamine (--ONH₂) or protectedhydroxylamine (--ONHP) groups. The hydroxylamine or protectedhydroxylamine groups are covalently bound directly to the solid supportor attached to the solid support by covalent bonds through a linkinggroup. The polymeric hydroxylamine resin compounds according to theprocess aspect of this invention are designated herein as ##STR42##wherein is a solid support as defined herein, L is absent or a linkinggroup and P is an amine protecting group.

"Linking group" and "linker" mean a group through which the amino oraminomethyl functionality may be covalently linked to the solid support.The linking group is generally inert to the reagents and reactionconditions described herein.

"Amine protecting group" means an easily removable group which is knownin the art to protect an amino group against undesirable reaction duringsynthetic procedures and to be selectively removable. The use ofN-protecting groups is well known in the art for protecting groupsagainst undesirable reactions during a synthetic procedure and many suchprotecting groups are known, CF, for example, T. H. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley &Sons, New York (1991), incorporated herein by reference. PreferredN-protecting groups are acyl, including formyl, acetyl, chloroacetyl,trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl,trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl,o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyland the like, and acyloxy including methoxycarbonyl,9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl,t-butyloxycarbonyl (BOC), 1,1-dimethylpropynyloxycarbonyl,benzyloxycarbonyl (CBZ), p-nitrophenylsulfinyl, p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, allyloxycarbonyl(Alloc), and the like.

"Carboxylic acid protecting group" and "acid protecting group" mean aneasily removable group which is known in the art to protect a carboxylicacid (--CO₂ H) group against undesirable reaction during syntheticprocedures and to be selectively removable. The use of carboxylic acidprotecting groups is well known in tile art and many such protectinggroups are known, CF, for example, T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons,New York (1991), incorporated herein by reference. Examples ofcarboxylic acid protecting groups include esters such as methoxymethyl,methylthiomethyl, tetrahydropyranyl, benzyloxymethyl, substituted andunsubstituted phenacyl, 2,2,2-trichloroethyl, tert-butyl, cinnamyl,substituted and uisubstituted benzyl, trimethylsilyl, allyl, and thelike, and amides and hydrazides including N,N-dimethyl, 7-nitroindolyl,hydrazide, N-phenylhydrazide, and the like. Especially preferredcarboxylic acid protecting groups are tert-butyl and benzyl.

"Hydroxy protecting group" means an easily removable group which isknown in the art to protect a hydroxy group against undesirable reactionduring synthetic procedures and to be selectively removable. The use ofhydroxy protecting groups is well known in the art and many suchprotecting groups are known, cf., for example, T. H. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley &Sons, New York (1991), incorporated herein by reference. Examples ofhydroxy protecting groups include ethers such as methyl; substitutedmethyl ethers such as methoxymethyl (MOM), methylthiomethyl (MTM),2-methoxyethoxymethyl (MEM), bis(2-chloroethoxy)methyl,tetrahydropyranyl (THP), tetrahydrothiopyranyl,4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydrothiofuranyl, and the like; substitutedethyl ethers such as 1-ethoxyethyl, 1-methyl-1-methoxyethyl,2-(phenylselenyl)ethyl, t-butyl, allyl, benzyl, o-nitrobenzyl,triphenylmethyl, a-naphthyidiphenylmethyl,p-methoxyphenyidiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl (tritylone),and the like; silyl ethers such as trimethylsilyl (TMS),isopropyidimethylsilyl, t-butyidimethylsilyl (TBDMS),t-butyidiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl,triisopropylsilyl, and the like; esters such as formate, acetate,trichloroacetate, phenoxyacetate, isobutyrate, pivaloate, adamantoate,benzoate, 2,4,6-trimethylbenzoate, and the like; and carbonates such asmethyl, 2,2,2-trichloroethyl, allyl, p-nitrophenyl, benzyl,p-nitrobenzyl, S-benzyl thiocarbonate, and the like.

"Amino acid" means an amino acid selected from the group consisting ofnatural and unnatural amino acids as defined herein.

"Natural amino acid" means an α-amino acid selected from the groupconsisting of alanine, valine, leucine, isoleucine, proline,phenylalanine, tryptophan, methionine, glycine, serine, threonine,cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine,aspartic acid and glutamic acid.

"Unnatural amino acid" means an amino acid for which there is no nucleicacid codon. Examples of unnatural amino acids include, for example, theD-isomers of the natural α-amino acids as indicated above; aminobutyricacid (Aib), 3-aminoisobutyric acid (bAib), norvaline (Nva), β-Ala,2-aminoadipic acid (Aad), 3-aminoadipic acid (bAad), 2-aminobutyric acid(Abu), γ-aminobutyric acid (Gaba), 6-aminocaproic acid (Acp),2,4-diaminobutryic acid (Dbu), α-aminopimelic acid, trimethylsilyl-Ala(TMSA), allo-isoleucine (aIle), norleucine (NIe), tert-Leu, citrulline(Cit), omithine (Orn), 2,2'-diaminopimelic acid) (Dpm),2,3-diaminopropionic acid (Dpr), α- or β-Nal, cyclohexyl-Ala (Cha),hydroxyproline, sarcosine (Sar), and the like; cyclic amino acids;N.sup.α -alkylated amino acids such as N.sup.α -methylglycine (MeGly),N.sup.α -ethylglycine (EtGly) and N.sup.α -ethylasparagine (EtAsn); andamino acids in which the α-carbon bears two side-chain substituents.

"Equivalent amino acid" means an amino acid which may be substituted foranother amino acid in the peptides according to the invention withoutany appreciable loss of function. In making such changes, substitutionsof like amino acids is made on the basis of relative similarity of sidechain substituents, for example regarding size, charge, hydrophilicity,hydropathicity and hydrophobicity as described herein.

"Peptide" and "polypeptide" mean a polymer in which the monomers arenatural or unnatural amino acid residues joined together through amidebonds. The term "peptide backbone" means the series of amide bondsthrough which the amino acid residues are joined. The term "amino acidresidue" means the individual amino acid units incorporated into thepeptides or polypeptides.

"Aliphatic" means a radical derived from a non aromatic C--H bond byremoval of the hydrogen atom. The aliphatic radical may be furthersubstituted by additional aliphatic or aromatic radicals as definedherein. Representative aliphatic groups include alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl,aralkyloxyalkyl, aralkyloxycarbonylalkyl, aralkyl, aralkynyl,aralkyloxyalkenyl, heteroaralkenyl, heteroaralkyl,heteroaralkyloxyalkenyl, heteroaralkyloxyalkyl, heteroaralkynyl, fusedarylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl,fused heteroarylcycloalkenyl, fused arylheterocyclyl, fusedheteroarylheterocyclyl, fused arylheterocyclenyl, fusedheteroarylheterocyclenyl, and the like. "Aliphatic", as used herein,also encompasses the residual, non-carboxyl portion of natural andunnatural amino acids as defined herein.

"Aromatic" means a radical derived from an aromatic C--H bond by removalof the hydrogen atom. Aromatic includes both aryl and heteroaryl ringsas defined herein. The aryl or heteroaryl ring may be furthersubstituted by additional aliphatic or aromatic radicals as definedherein. Representative aromatic groups include aryl, fusedcycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fusedheterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fusedcycloalkenylheteroaryl, fused heterocyclenylheteroaryl, fusedheterocyclylheteroaryl, and the like.

"Acid bioisostere" means a group which has chemical and physicalsimilarities producing broadly similar biological properties (seeLipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p283"Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993,33,p576-579"Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao,1995, p34-38 "Bioisosteric Replacement And Development Of Lead CompoundsIn Drug Design"; Graham, Theochem, 1995, 343, p105-109 "TheoreticalStudies Applied To Drug Design: ab initio Electronic Distributions InBioisosteres"). Examples of suitable acid bioisosteres include:--C(═O)--NH--OH, --C(═O)--CH₂ OH, --C(═O)--CH₂ SH, --C(═O)--NH--CN,sulpho, phosphono, alkylsulfonylcarbamoyl, tetrazolyl,arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl,3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl orheterocyclic phenols such as 3-hydroxyisoxazolyl and3-hydoxy-1-methylpyrazolyl.

"Acyl" means an H--CO-- or alkyl-CO-- group wherein the alkyl group isas herein described. Preferred acyls contain a lower alkyl. Exemplaryacyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,butanoyl and palmitoyl.

"Acylamino" is an acyl-NH-- group wherein acyl is as defined herein.

"Alkenoyl" means an alkenyl-CO-- group wherein alkenyl is as definedherein.

"Alkenyl" means a straight or branched aliphatic hydrocarbon group of 2to about 15 carbon atoms which contains at least one carbon-carbondouble bond. Preferred alkenyl groups have 2 to about 12 carbon atoms;more preferred alkenyl groups have 2 to about 4 carbon atoms. Thealkenyl group is optionally substituted with one or more alkyl groupsubstituents as defined herein. Representative alkenyl groups includeethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl,heptenyl, octenyl, cyclolhexylbutenyl and decenyl.

"Alkenyloxy" means an alkenyl-O-- group wherein the alkenyl group is asherein described. Representative alkenyloxy groups include allyloxy or3-butenyloxy.

"Alkoxy" means an alkyl-O-- group wherein the alkyl group is as definedherein. Representative alkoxy groups include methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, heptoxy, and the like.

"Alkoxyalkyl" means an alkyl-O-alkylene- group wherein alkyl andalkylene are as defined herein. Representative alkoxyalkyl groupsinclude methoxyethyl, ethoxymethyl, n-butoxymethyl andcyclopentylmethyloxyethyl.

"Alkoxyalkoxy" means an alkyl-O-alkylenyl-O-- group. Representativealkoxyalkoxy include methoxymethoxy, methoxyethoxy, ethoxyethoxy, andthe like.

"Alkoxycarbonyl" means an ester group; i.e. an alkyl-O--CO-- groupwherein alkyl is as defined herein. Representative alkoxycarbonyl groupsinclude methoxycarbonyl, ethoxycarbonyl, t-butyloxycarbonyl, and thelike.

"Alkoxycarbonylalkyl" means an alkyl-O-CO-alkylene- group wherein alkyland alkylene are as defined herein. Representative alkoxycarbonylalkylinclude methoxycarbonylmethyl, and ethoxycarbonylmethyl, methoxycarbonylethyl, and the like.

"Alkyl" means an aliphatic hydrocarbon group which may be straight orbranched having about 1 to about 20 carbon atoms in the chain. Preferredalkyl groups have 1 to about 12 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl are attached to a linear alkyl chain. "Lower alkyl" means about 1to about 4 carbon atoms in the chain which may be straight or branched.The alkyl is optionally substituted with one or more "alkyl groupsubstituents" which may be the same or different, and include halo,cycloalkyl, hydroxy, alkoxy, amino, carbamoyl, acylamino, aroylamino,carboxy, alkoxycarbonyl, aralkyloxycarbonyl, orheteroaralkyloxycarbonyl. Representative alkyl groups include methyl,trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl,carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, andpyridylmethyloxycarbonylmethyl.

"Alkylene" means a straight or branched bivalent hydrocarbon chain of 1to about 6 carbon atoms. The alkylene is optionally substituted with oneor more "alkylene group substituents" which may be the same ordifferent, and include halo, cycloalkyl, hydroxy, alkoxy, carbamoyl,carboxy, cyano, aryl, heteroaryl or oxo. The alkylene is optionallyinterrupted by, i.e., a carbon thereof is substituted for, --O--,--S(O)_(m) (where m is 0-2), phenylene or --NR¹ -- (where R¹ is loweralkyl). Preferred alkylene groups are the lower alkylene groups having 1to about 4 carbon atoms. Representative alkylene groups includemethylene, ethylene, and the like.

"Alkenylene" means a straight or branched bivalent hydrocarbon chaincontaining at least one carbon--carbon double bond. The alkenylene isoptionally substituted with one or more "alkylene group substituents" asdefined herein. The alkenylene is optionally interrupted by, i.e., acarbon thereof is substituted for, --O--, --S(O)_(m) (where m is 0-2),phenylene or --NR¹ -- (where R¹ is lower alkyl). Representativealkenylene include --ClH═CH--, --CH₂ CH═CH--, --C(CH₃)═CH--, --CH₂CH═CHCH₂ --, and the like.

"Alkynylene" means a straight or branched bivalent hydrocarbon chaincontaining at least one carbon-carbon triple bond. The alkynylene isoptionally substituted with one or more "alkylene group substituenits"as defined herein. The alkynylene is optionally interrupted by, i.e., acarbon thereof is substituted for, --O--, --S(O)_(m) (where m is 0-2),phenylene or --NR¹ -- (where R¹ is lower alkyl). Representativealkynylene include --CH.tbd.CH--, --CH.tbd.CH--CH₂ --,--CH.tbd.CH--CH(CH₃)--, and the like.

"Alkylsulfinyl" means an alkyl-SO-- group wherein the alkyl group is asdefined above. Preferred alkylsulfinyl groups are those wherein thealkyl group is lower alkyl.

"Alkylsuffonyl" means an alkyl-SO₂ -- group wherein the alkyl group isas defined herein. Preferred alkylsulfonyl groups are those wherein thealkyl group is lower alkyl.

"Alkylsulfonylcarbamoyl" means an alkyl-SO₂ --NH--CO-- group whereinalkyl group is defined wherein. Preferred alkylsulfonylcarbamoyl groupsare those wherein the alkyl group is lower alkyl.

"Alkylthio" means an alkyl-S-- group wherein the alkyl group is asdefined herein. Preferred alkylthio groups are those wherein the alkylgroup is lower alkyl. Representative alkylthio groups includemethylthio, ethylthio, i-propylthio, heptylthio, and the like.

"Alkynyl" means a straight or branched aliphatic hydrocarbon group of 2to about 15 carbon atoms which contains at least one carbon-carbontriple bond. Preferred alkynyl groups have 2 to about 12 carbon atoms.More preferred alkynyl groups contain 2 to about 4 carbon atoms. "Loweralkynyl" means alkynyl of 2 to about 4 carbon atoms. The alkynyl groupmay be substituted by one or more alkyl group substituents as definedherein. Representative alkynyl groups include ethynyl, propynyl,n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl,decynyl, and the like.

"Alkynyloxy" means an alkynyl-O-- group wherein the alkynyl group isdefined herein. Representative alkynyloxy groups include propynyloxy,3-butynyloxy, and the like.

"Alkynyloxyalkyl" means alkynyl-O-alkylene- group wherein alkynyl andalkylene are defined herein.

"Amidino" or "amidine" means a group of formula ##STR43## wherein R² ishydrogen; R²⁷ O₂ C-- wherein R²⁷ is hydrogen, alkyl, aralkyl orheteroaralkyl; R²⁷ --; R²⁷ C(O)--; cyano; alkyl; nitro; or amino, andR²⁶ is selected from hydrogen; alkyl; aralkyl; and heteroaralkyl.

"Amino" means a group of formula Y¹ Y² N-- wherein Y¹ and Y² areindependently hydrogen; acyl; or alkyl, or Y¹ and Y² taken together withthe N through which Y¹ and Y² are linked form a 4 to 7 memberedazaheterocyclyl. Representative amino groups include amino (H₂ N--),methylamino, dimethylamino, diethylamino, and the like.

"Aminoalkyl" means an amino-alkylene- group wherein amino and alkyleneare defined herein. Representative aminoalkyl groups includeaminomethyl, aminoethyl, dimethylaminomethyl, and the like.

"Aralkenyl" means a aryl-alkenylene- group wherein aryl and alkenyleneare define herein. Preferred aralkenyls contain a lower alkenylenemoiety. A representative aralkenyl group is 2-phenethenyl.

"Aralkyloxy" means an aralkyl-O-- group wherein aralkyl is definedherein. Representative aralkoxy groups include benzyloxy,naphth-1-ylmethoxy, naphth-2-ylmethoxy, and the like.

"Aralkyloxyalkyl" means an aralkyl-O-alkylene- group wherein aralkyl andalkylene are defined herein. A representative aralkyloxyalkyl group isbenzyloxyethyl.

"Aralkyloxycarbonyl" means an aralkyl-O--CO-- group wherein aralkyl isdefined herein. A representative aralkoxycarbonyl group isbenzyloxycarbonyl.

"Aralkyloxycarbonylalkyl" means an aralkoxycarbonyl-alkylene- whereinaralkyloxycarbonyl and alkylene are defined herein. Representativearalkoxycarbonylalkyls include benzyloxycarbonylmethyl,benzyloxycarbonylethyl.

"Aralkyl" means an aryl-alkylenyl--Preferred alkylsulfonylcarbamoylgroups are those wherein the alkyl group is lower alkyl group. Preferredaralkyls contain a lower alkyl moiety. Representative aralkyl groupsinclude benzyl, 2-phenethyl, naphthlenemethyl, and the like.

"Aralkyloxyalkenyl" means an aralkyl-O-alkenylene- group wherein aralkyland alkenylene are defined herein. A representative aralkyloxyalkenylgroup is 3-benzyloxyallyl.

"Aralkylsulfonyl" means an aralkyl-SO₂ -- group wherein aralkyl isdefined herein.

"Aralkylsulfinyl" means an aralkyl-SO-- group wherein aralkyl is definedherein.

"Aralkylthio" means an aralkyl-S-- group wherein aralkyl is definedherein. A representative aralkylthio group is benzylthio.

"Aroyl" means an aryl-CO-- group wherein aryl is defined herein.Representative aroyl include benzoyl, naphth-1-oyl and naphth-2-oyl.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system ofabout 3 to about 10 carbon atoms, preferably of about 5 to about 10carbon atoms. Preferred cycloalkyl rings contain about 5 to about 6 ringatoms. The cycloalkyl is optionally substituted with one or more "ringsystem substituents" which may be the same or different, and are asdefined herein, or where R¹⁸ is a substituted cycloalkyl, the cycloalkylis substituted by one or more (e.g. 1, 2 or 3) substituents chosen fromOR²³, SR²⁴, SOR²⁴, SO₂ R²⁴, NH₂, NR²² R²⁴, ═NOR²⁴, ═NOH, ═NNHR²⁴,═NOCONHR²⁴, ═NCO₂ R²⁴, SOR²⁴, NHCOR²⁴, NHSO₂ R²⁴, SO₂ NR²² R²⁴, R²³,CONHR²⁴, CONHCH₂ CO₂ R²², CONR²⁴ R²², N₃ or azaheterocyclyl; wherein R²³is as defined herein; R²³ is hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl; and R²⁴ is alkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl. Representative monocyclic cycloalkyl includecyclopentyl, cyclohexyl, cycloheptyl, and the like. Representativemulticyclic cycloalkyl include 1-decalin, norbornyl, adamantyl, and thelike. The prefix spiro before cycloalkyl means that geminal substituentson a carbon atom are replaced to form 1,1-cycloalkyl. "Cycloalkylene"means a bivalent cycloalkyl having about 4 to about 8 carbon atoms.Preferred cycloalkylenyl groups include 1,2-, 1,3-, or 1,4- cis ortrans-cyclohexylene.

"Cycloalkenyl" means a non-aromatic mono- or multicyclic ring system ofabout 3 to about 10 carbon atoms, preferably of about 5 to about 10carbon atoms which contains at least one carbon--carbon double bond.Preferred cycloalkylene rings contain about 5 to about 6 ring atoms. Thecycloalkenyl is optionally substituted with one or more "ring systemsubstituents" which may be the same or different, and are as definedherein. Representative monocyclic cycloalkenyl include cyclopentenyl,cyclohexenyl, cycloheptenyl, and the like. A representative multicycliccycloalkenyl is norbornylenyl.

"Cyclocarbamoylalkyl" means a compound of formula ##STR44## in which thecyclocarbamoyl group consists of the oxooxazaheterocyclyl ring moiety,and the alkylene group is as defined herein. The alkylene moiety may beattached to the carbamoyl through either a carbon atom or the nitrogenatom of the carbamoyl moiety. An exemplary cyclocarbamoylalkyl group isN-oxazolidinylpropyl.

"Cycloimidylalkyl" means a compound of formula ##STR45## in which theimide group consists of the oxodiazaheterocyclyl ring moiety, andalkylene is as defined herein. The alkylene moiety may be attached tothe carbamoyl through either a carbon atom or nitrogen atom of thecarbamoyl moiety. An exemplary cycloimidylalkyl group isN-phthalimidepropyl.

"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ringsystem of about 3 to about ring atoms, preferably about 5 to about 10ring atoms, in which one or more of the atoms in the ring system is/areelement(s) other than carbon, for example nitrogen, oxygen or sulfuratoms, and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia beforeheterocyclenyl means that at least a nitrogen, oxygen or sulfur atomrespectively is present as a ring atom. The heterocyclenyl is optionallysubstituted by one or more ring system substituents, wherein "ringsystem substituent" is as defined herein. The nitrogen or sulphur atomof the heterocyclenyl is optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Representative monocyclicazaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine,1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, and the like. Representativeoxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl,fluorodihydrofuranyl, and the like. A representative multicyclicoxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Representativemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like.

"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclicring system of about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is/are element(s) other than carbon, for example nitrogen, oxygenor sulfur. Preferred heterocyclyls contain about 5 to about 6 ringatoms. The prefix aza, oxa or thia before heterocyclyl means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The heterocyclyl is optionally substituted by one or more"ring system substituents" which may be the same or different, and areas defined herein, or wherein R¹⁸ is a substituted heterocyclyl, theheterocyclyl is substituted the ring carbon atoms by one or more (e.g.1, 2 or 3) substituents chosen from oxo, cyano, CO₂ R²², CONHCH₂ CO₂R²², aryl, arylalkyl, alkyl or hydroxyalkyl, or is substituted on a ringnitrogen atom by a substituent chosen from R²², (CH₂)_(n) CO₂ H,(CH₂)_(n) CO₂ R²⁴, (CH₂)_(n) CONR²² R²⁴, (CH₂)_(n) COR²⁴, CONH₂,CONHR²⁴, COR²⁴, SO₂ R²⁴, or OR²⁴, wherein R²² and R²⁴ are as definedherein. The nitrogen or sulphur atom of the heterocyclyl is optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.Representative monocyclic heterocyclyl rings include piperidyl,pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

"Aryl" means an aromatic monocyclic or multicyclic ring system of 6 toabout 14 carbon atoms, preferably of about 6 to about 10 carbon atoms.The aryl is optionally substituted with one or more "ring systemsubstituents" which may be the same or different, and are as definedherein. Representative aryl groups include phenyl and naphthyl.

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system ofabout 5 to about 14 ring atoms, preferably about 5 to about 10 ringatoms, in which one or more of the atoms in the ring system is/areelement(s) other than carbon, for example nitrogen, oxygen or sulfur.Preferred heteroaryls contain about 5 to about 6 ring atoms. The"heteroaryl" is optionally substituted by one or more "ring systemsubstituents" which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before heteroaryl means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. A nitrogen atom of a heteroaryl is optionally oxidized to thecorresponding N-oxide. Representative heteroaryls include pyrazinyl,furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl,triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,phthalazinyl, imidazo[ 1,2-a]pyridine, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

"Fused arylcycloalkenyl" means a radical derived from a fused aryl andcycloalkenyl as defined herein by removal of hydrogen atom from thecycloalkenyl portion. Preferred fused arylcycloalkenyls are thosewherein aryl is phenyl and the cycloalkenyl consists of about 5 to about6 ring atoms. The fused arylcycloalkenyl is optionally substituted byone or more ring system substituents, wherein "ring system substituent"is as defined herein. Representative fused arylcycloalkenyl include1,2-dihydronaphthylene, indene, and the like, in which the bond to theparent moiety is through a non-aromatic carbon atom.

"Fused cycloalkenylaryl" means a radical derived from a fusedarylcycloalkenyl as defined herein by removal of hydrogen atom from thearyl portion. Representative fused cycloalkenylaryl are as describedherein for a fused arylcycloalkenyl, except that the bond to the parentmoiety is through an aromatic carbon atom.

"Fused arylcycloalkyl" means a radical derived from a fused aryl andcycloalkyl as defined herein by removal of a hydrogen atom from thecycloalkyl portion. Preferred fused arylcycloalkyls are those whereinaryl is phenyl and the cycloalkyl consists of about 5 to about 6 ringatoms. The fused arylcycloalkyl is optionally substituted by one or morering system substituents, wherein "ring system substituent" is asdefined herein. Representative fused arylcycloalkyl includes1,2,3,4-tetrahydronaphthyl, and the like, in which the bond to theparent moiety is through a non-aromatic carbon atom.

"Fused cycloalkylarvi" means a radical derived from a fusedarylcycloalkyl as defined herein by removal of a hydrogen atom from thearyl portion. Representative fused cycloalkylaryl are as describedherein for a fused arylcycloalkyl radical, except that the bond to theparent moiety is through an aromatic carbon atom.

"Fused arylheterocyclenyl" means a radical derived from a fused aryl andheterocyclenyl as defined herein by removal of a hydrogen atom from theheterocyclenyl portion. Preferred fused arylheterocyclenyls are thosewherein aryl is phenyl and the heterocyclenyl consists of about 5 toabout 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl portion of the fused arylheterocyclenyl means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The fused arylheterocyclenyl is optionally substituted by oneor more ring system substituents, wherein "ring system substituent" isas defined herein. The nitrogen or sulphur atom of the heterocyclenylportion of the fused arylheterocyclenyl is optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Representative fusedarylheterocyclenyl include 3H-indolinyl, 1H-2-oxoquinolyl,2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl,1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, and the like, inwhich the bond to the parent moiety is through a non-aromatic carbonatom.

"Fused heterocyclenylaryl" means a radical derived from a fusedarylheterocyclenyl as defined herein by removal of a hydrogen atom fromthe aryl portion. Representative fused heterocyclenylaryl are as definedherein for a fused arylheterocyclenyl radical, except that the bond tothe parent moiety is through an aromatic carbon atom.

"Fused arylheterocyclyl" means a radical derived from a fused aryl andheterocyclyl as defined herein by removal of a hydrogen atom from theheterocyclyl portion. Preferred fused arylheterocyclyls are thosewherein aryl is phenyl and the heterocyclyl consists of about 5 to about6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means thatat least a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The fused arylheterocyclyl is optionally substituted by oneor more ring system substituents, wherein "ring system substituent" isas defined herein. The nitrogen or sulphur atom of the heterocyclylportion of the fused arylheterocyclyl is optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Representative preferredfused arylheterocyclyl ring systems include phthalimide,1,4-benzodioxane, indolinyl, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydroquinoline, 1H-2,3-dibydroisoindolyl,2,3-dihydrobenz[g]isoindolyl, 1,2,3,4-tetrahydrobenz[g]isoquinolinyl,and the like, in which the bond to the parent moiety is through anon-aromatic carbon atom.

"Fused heterocyclylaryl" means a radical derived from a fusedaryheterocyclyl as defined herein by removal of a hydrogen atom from theheterocyclyl portion. Representative preferred fused heterocyclylarylring systems are as described for fused arylheterocyclyl, except thatthe bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylcycloalkenyl" means a radical derived from a fusedheteroaryl and cycloalkenyl as defined herein by removal of a hydrogenatom from the cycloalkenyl portion. Preferred fusedheteroarylcycloalkenyls are those wherein the heteroaryl and thecycloalkenyl each contain about 5 to about 6 ring atoms. The prefix aza,oxa or thia before heteroaryl means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The fusedheteroarylcycloalkenyl is optionally substituted by one or more ringsystem substituents, wherein "ring system substituent" is as definedherein. The nitrogen atom of the heteroaryl portion of the fusedheteroarylcycloalkenyl is optionally oxidized to the correspondingN-oxide. Representative fused heteroarylcycloalkenyl include5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl,5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl,4,5-dihydrobenzoxazolyl, and the like, in which the bond to the parentmoiety is through a non-aromatic carbon atom.

"Fused cycloalkenylheteroaryl" means a radical derived from a fusedheteroarylcycloalkenyl as defined herein by removal of a hydrogen atomfrom the heteroaryl portion. Representative fused cycloalkenylheteroarylare as described herein for fused heteroarylcycloalkenyl, except thatthe bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylcycloalkyl" means a radical derived from a fusedheteroaryl and cycloalkyl as defined herein by removal of a hydrogenatom from the cycloalkyl portion. Preferred fused heteroarylcycloalkylsare those wherein the heteroaryl thereof consists of about 5 to about 6ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms.The prefix aza, oxa or thia before heteroaryl means that at least anitrogen, oxygen or sulfur atom is present respectively as a ring atom.The fused heteroarylcycloalkyl is optionally substituted by one or morering system substituents, wherein "ring system substituent" is asdefined herein. The nitrogen atom of the heteroaryl portion of the fusedheteroarylcycloalkyl is optionally oxidized to the correspondingN-oxide. Representative fused heteroarylcycloalkyl include5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl,5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl,4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl,1H-4-oxa-1,5-diazanaphthalen-2-onyl,1,3-dihydroimidizole-[4,5]-pyridin-2-onyl, and the like, in which thebond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkylheteroaryl" means a radical derived from a fusedheteroarylcycloalkyl as defined herein by removal of a hydrogen atomfrom the heteroaryl portion. Representative fused cycloalkylheteroarylare as described herein for fused heteroarylcycloalkyl, except that thebond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylheterocyclenyl" means a radical derived from a fusedheteroaryl and heterocyclenyl as defined herein by the removal of ahydrogen atom from the heterocyclenyl portion. Preferred fusedheteroarylheterocyclenyls are those wherein the heteroaryl thereofconsists of about 5 to about 6 ring atoms and the heterocyclenylconsists of about 5 to about 6 ring atoms. The prefix aza, oxa or thiabefore heteroaryl or heterocyclenyl means that at least a nitrogen,oxygen or sulfur atom is present respectively as a ring atom. The fusedheteroarylheterocyclenyl is optionally substituted by one or more ringsystem substituents, wherein "ring system substituent" is as definedherein. The nitrogen atom of the heteroaryl portion of the fusedheteroarylheterocyclenyl is optionally oxidized to the correspondingN-oxide. The nitrogen or sulphur atom of the heterocyclenyl portion ofthe fused heteroarylheterocyclenyl is optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Representative fusedheteroarylheterocyclenyl include 7,8-dihydro[1,7]naphthyridinyl,1,2-dihydro[2,7]naphthyridinyl, 6,7-dihydro-3 H-imidazo[4,5-c]pyridyl,1,2-dihydro-1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl,1,2-dihydro-1,7-naphthyridinyl, 1,2-dihydro-1,8-naphthyridinyl,1,2-dihydro-2,6-naphthyridinyl, and the like, in which the bond to theparent moiety is through a non aromatic carbon atom.

"Fused heterocyclenylheteroaryl" means a radical derived from a fusedheteroarylheterocyclenyl as defined herein by the removal of a hydrogenatom from the heteroaryl portion. Representative fusedheterocyclenyiheteroaryl are as described herein for fusedheteroarylheterocyclenyl, except that the bond to the parent moiety isthrough an aromatic carbon atom.

"Fused heteroarylheterocyclyl" means a radical derived from a fusedheteroaryl and heterocyclyl as defined herein, by removal of a hydrogenatom from the heterocyclyl portion. Preferred fusedheteroarylheterocyclyls are those wherein the heteroaryl thereofconsists of about 5 to about 6 ring atoms and the heterocyclyl consistsof about 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheteroaryl or heterocyclyl portion of the fused heteroarylheterocyclylmeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The fused heteroarylheterocyclyl is optionallysubstituted by one or more ring system substituents, wherein "ringsystem substituent" is as defined herein. The nitrogen atom of theheteroaryl portion of the fused heteroarylheterocyclyl is optionallyoxidized to the corresponding N-oxide. The nitrogen or sulphur atom ofthe heterocyclyl portion of the fused heteroarylheterocyclyl isoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Representative fused heteroarylheterocyclyl include2,3-dihydro-1H pyrrol[3,4-b]quinolin-2-yl,1,2,3,4-tetrahydrobenz[b][1,7]naphthyridin-2-yl,1,2,3,4-tetrahydrobenz[b][1,6]naphthyridin-2-yl,1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl,1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl,2,3,-dihydro-1H-pyrrolo[3,4-b]indol-2-yl,1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl,1H-2,3,4,5-tetrahydroazepino[4,3-b]indol-3-yl, 1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2 yl,5,6,7,8-tetrahydro[1,7]napthyridinyl,1,2,3,4-tetrahydro[2,7]naphthyridyl,2,3-diliydro[1,4]dioxino[2,3-b]pyridyl,2,3-dihydro[1,4]dioxino[2,3-b]pryidyl,3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl,1,2,3,4-tetrahydro[1,5]napthyridinyl,1,2,3,4-tetrahydro[1,6]napthyridinyl,1,2,3,4-tetrahydro[1,7]napthyridinyl,1,2,3,4-tetrahydro[1,8]napthyridinyl,1,2,3,4-tetrahydro[2,6]napthyridinyl, and the like, in which the bond tothe parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclylheteroaryl" means a radical derived from a fusedheteroarylheterocyclyl as defined herein, by removal of a hydrogen atomfrom the heteroaryl portion. Representative fused heterocyclylheteroarylare as described herein for fused heteroarylheterocyclyl, except thatthe bond to the parent moiety is through an aromatic carbon atom.

"Aralkynyl" means an aryl-alkynylene- group wherein aryl and alkynyleneare defined herein. Representative aralkynyl groups includephenylacetylenyl and 3-phenylbut-2-ynyl.

"Aryidiazo" means an aryl-N═N-- group wherein aryl is defined herein.Representative aryidiazo groups include phenyidiazo and naphthyidiazo.

"Arylcarbamoyl" means an aryl-NHCO-- group, wherein aryl is definedherein.

"Benzyl" means a phenyl-CH₂ -- group. Substituted benzyl means a benzylgroup in which the phenyl ring is substituted with one or more ringsystem substituents. Representative benzyl include 4-bromobenzyl,4-methoxybenzyl, 2,4-dimethoxybenzyl, and the like.

"Carbamoyl" means a group of formula Y¹ Y² NCO--wherein Y¹ and Y² aredefined herein. Representative carbamoyl groups include carbamyl (H₂NCO--), dimethylaminocarbamoyl (Me₂ NCO--), and the like.

"Carboxy" and "carboxyl" mean a HO(O)C-- group (i.e. a carboxylic acid).

"Carboxyalkyl" means a HO(O)C-alkylene- group wherein alkylene isdefined herein. Representative carboxyalkyls include carboxymethyl andcarboxyethyl.

"Cycloalkyloxy" means a cycloalkyl-O-- group wherein cycloalkyl isdefined herein. Representative cycloalkyloxy groups includecyclopentyloxy, cyclohexyloxy, and the like.

"Diazo" means a bivalent --N═N-- radical.

"Ethylenyl" means a --CH═CH-- group.

"Halo" or "halogen" mean fluoro, chloro, bromo, or iodo.

"Heteroaralkenyl" means a heteroaryl-alkenylene- group whereinheteroaryl and alkenylene are defined herein. Preferred heteroaralkenylscontain a lower alkenylene moiety. Representative heteroaralkenyl groupsinclude 4-pyridylvinyl, thienylethenyl, pyridylethenyl,imidazolylethenyl, pyrazinylethenyl, and the like.

"Heteroaralkyl" means a heteroaryl-alkylene- group wherein heteroaryland alkylene are defined herein. Preferred heteroaralkyls contain alower alkylene group. Representative heteroaralkyl groups includethienylmethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, and thelike.

"Heteroaralkyloxy" means an heteroaralkyl-O-- group whereinheteroaralkyl is defined herein. A representative heteroaralkyloxy groupis 4-pyridylmethyloxy.

"Heteroaralkyloxyalkenyl" means a heteroaralkyl-O-alkenylene- groupwherein heteroaralkyl and alkenylene are defined herein. Arepresentative heteroaralkyloxyalkenyl group is 4-pyridylmethyloxyallyl.

"Heteroaralkyloxyalkyl" means a heteroaralkyl-O-alkylene- group whereinheteroaralkyl and alkylene are defined herein. A representativeheteroaralkyloxy group is 4-pyridylmethyloxyethyl.

"Heteroaralkynyl" means an heteroaryl-alkynylene- group whereinheteroaryl and alkynylene are defined herein. Preferred heteroaralkynylscontain a lower alkynylene moiety. Representative heteroaralkynyl groupsinclude pyrid-3-ylacetylenyl, quinolin-3-ylacetylenyl, 4-pyridylethynyl,and the like.

"Heteroaroyl" means an means a heteroaryl-CO-- group wherein heteroarylis defined herein. Representative heteroaroyl groups includethiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, pyridinoyl, and the like.

"Heteroaryidiazo" means an heteroaryl-N═N-- group wherein heteroaryl isas defined herein.

"Heteroarylsulphonylcarbamoyl" means a heteroaryl-SO₂ --NH--CO-- groupwherein heteroaryl is defined herein.

"Heterocyclylalkyl" means a heterocyclyl-alkylene- group whereinheterocyclyl and alkylene are defined herein. Preferredheterocyclylalkyls contain a lower alkylene moiety. A representativeheteroaralkyl group is tetrahydropyranylmethyl.

"Heterocyclylalkyloxyalkyl" means a heterocyclylalkyl-O-alkylene groupwherein heterocyclylalkyl and alkylene are defined herein. Arepresentative heterocyclylalkyloxyalkyl group istetrahydropyranylmethyloxymethyl.

"Heterocyclyloxy" means a heterocyclyl-O-- group wherein heterocyclyl isdefined herein. Representative heterocyclyloxy groups includequinuclidyloxy, pentamethylenesulfideoxy, tetrahydropyranyloxy,tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy,7-oxabicyclo[2.2.1]heptanyloxy, liydroxytetrahydropyranyloxy,hydroxy-7-oxabicyclo[2.2.1]heptanyloxy, and the like.

"Hydroxyalkyl" means an alkyl group as defined herein substituted withone or more hydroxy groups. Preferred hydroxyalkyls contain lower alkyl.Representative hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

"N-oxide" means a ##STR46## group.

"Oxo" means a group of formula >C═O (i.e., a carbonyl group).

"Phenoxy" means a phenyl-O-- group wherein the phenyl ring is optionallysubstituted with one or more ring system substituents as defined herein.

"Phenylene" means a -phenyl- group wherein the phenyl ring is optionallysubstituted with one or more ring system substituents as defined herein.

"Phenylthio" means a phenyl-S-- group wherein the phenyl ring isoptionally substituted with one or more ring system substituents asdefined herein.

"Pyridyloxy" means a pyridyl-O-- group wherein the pyridyl ring isoptionally substituted with one or more ring system substituents asdefined herein.

"Ring system substituent" means a substituent which optionally replacesa hydrogen CH or NH constituent of an aromatic or non-aromatic ringsystem. Ring system substituents are selected from the group consistingof aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl,heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy,aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, aryidiazo, heteroaryidiazo, amidino, Y¹ Y² N--, Y¹ Y²N-alkyl-, Y¹ Y² NCO-- or Y¹ Y² NSO₂ --, wherein Y¹ and Y² areindependently hydrogen, alkyl, aryl, and aralkyl, or where thesubstituent is Y¹ Y² N-- or Y¹ Y² N-alkyl- then one of Y¹ and Y² is acylor aroyl and the other of Y¹ and Y² is hydrogen, alkyl, aryl, andaralkyl. When a ring system is saturated or partially saturated, the"ring system substituent" further comprises methylene (H2C═), oxo (O═)and thioxo (S═).

"Sulfamoyl" means a group of formula Y¹ Y² NSO₂ -- wherein Y¹ and Y² aredefined herein. Representative sulfamoyl groups are sulfamoyl (H₂ NSO₂--) and dimethylsulfamoyl (Me₂ NSO₂ --).

Preferred Embodiments

A process for the preparation of aldehydes and ketones according to thisinvention is outlined in Scheme 1 wherein R_(a) and R_(b) independentlyrepresent any aliphatic or aromatic group amenable to the solvents andreagents utilized in the processes described herein. The groups R_(a)and R_(b) may be further substituted and may contain functional groupssuitable for further chemical transformations while attached to thehydroxylamine resin. Such functional groups may be suitable protected toprevent interference with the reactions described below. For acomprehensive treatise on the protection and deprotection of commonfunctional groups see T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991),incorporated herein by reference. R_(c) represents any aliphatic oraromatic group suitable for use as an organometallic reagent. ##STR47##

According to the foregoing Scheme 1, a polymeric hydroxylamine resincompound 1 is coupled with a carboxylic acid derivative of formula R_(a)CO₂ H to form the polymeric hydroxamic acid resin compound 2. Thecoupling reaction is accomplished in the presence of an activating agentas is known in the art of peptide synthesis. Representative activatingagents include isopropyl chloroformate, diisopropylcarbodiimide (DIC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),1-hydroxybenzotriazole (HOBT), bis(2-oxo-3-oxazolidinyl)-phosphonicchloride (BOP-CI),benzotriazole-1-yloxy-tris((dimethylamino)phosphonium)hexafluorophosphate(BOP), benzotriazole-1-yloxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBROP), bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP),2-(1H-benzotriazole-1-yl)-1.1.3.3-tetramethyluronium tetrafluoroborate(TBTU), 2-(1H-benzotriazole-1-yl)-1.1.3.3-tetramethyluroniumhexafluoroborate (HBTU),2-[2-oxo-1-(2H)-pyridyl]-1,1,3,3-bispentamethyleneuronoiumtetrafluoroborate (TOPPipU), N,N'-dicyclohexylcarbodiimide (DCC), andthe like. Suitable solvents for the coupling reaction includedichloromethane, DMF, DMSO, THF, and the like. Coupling times range fromabout 2 to about 24 hours, depending upon the resin and carboxylic acidderivative to be coupled, activating agent, solvent and temperature. Thecoupling is accomplished at from about -10° C. to about 50° C.,preferably at about ambient temperature.

The coupling reaction is preferably accomplished at ambient temperaturein DMF using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideover about 12 hours.

The polymeric hydroxamic acid resin compound 2 is then alkylated with analkylating agent of formula R_(b) LG, where LG is a leaving group, inthe presence of a non-nucleophilic base such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in an inert organic solventsuch as toluene to form the N-alkylated polymeric hydroxamic acid resincompound 3. The alkylating agent R_(b) LG may be added in an equimolaramount to an excess of to about 25 molar equivalents. About 15 molarequivalents is preferred. The non-nucleophilic base may be added in anequimolar amount to an excess of to about 10 molar equivalents. About 5molar equivalents is preferred. The leaving group LG is any groupamenable to nucleophilic displacement by the nitrogen atom of thepolymeric hydroxamic acid resin compound 2 under the reaction conditionsdescribed above. A preferred leaving group is halogen. A sample of theN-alkylated polymeric hydroxamic acid resin compound 3 may be subjectedto acidolysis to cleave the substituted hydroxamic acid to confirm thatthe reaction proceeded satisfactorily.

Reaction of the polymeric N-alkylated hydroxamic acid resin compound 3with an organometallic reagent of formula R_(c) M, wherein R_(c) is analiphatic or aromatic anion and M is a metal cation, followed by acidhydrolysis provides the ketone 4. Preferred organometallic reagents areorganolithium reagents of formula R_(c) M and Grignard reagents offormula R_(c) MgX wherein X is halogen. In a preferred preparation ofketones according to this aspect of the invention, the polymericN-alkylated hydroxamic acid resin compound 3 is treated with R_(c) MgXin diethyl ether at ambient temperature over about 18 hours, and thereaction mixture is then quenched by addition of aqueous HCl or aqueousKHSO₄ to liberate the ketone 4.

Aldehydes are prepared by treatment of the polymeric N-alkylatedhydroxamic acid resin compound 3 with a hydride reducing agent, followedby acid hydrolysis as shown in Scheme 1 above. Representative hydridereducing agents include LiAlH₄, (iso-Bu)₂ AIH, LiAlH(O-t-Bu)₃, LiAlH₄--EtOH, LiAlH₄ --MeOH, and the like. Preferred reducing agents areLiAlH₄ and LiAlH₄ --MeOH. The acid hydrolysis is preferably accomplishedaqueous KHSO₄.

As shown in Scheme 1, the N-alkylated polymeric hydroxamic acid resincompound 3 is a Weinreb-like amide useful for the synthesis of aldehydesand ketones (S. Nahm and S. Weinreb, Tet. Lett. 1981, 22, 3815-3818).This N-alkylated polymeric hydroxamic acid resin compound has advantagesover the previous examples of resin bound Weinreb-like amides (SeeFehrentz et al., Tet. Lett., 1995, 36, 7871-7874 and Dinh et al., Tet.Lett., 1996, 37, 1161-1164) in that it can be N-alkylated with bulkylipophilic groups such as benzyl, substituted benzyl, naphthyl or anyalkyl group necessary to optimize the reaction on the solid phase. TheN-benzyl-O-methylpolystyrenyl moiety, for example, is well suited toform a stable metal chelated intermediate. The lipophilic benzyl groupis believed to help shield the chelate adding to its stability.

A preferred process for the preparation of aldehydes and ketones isoutlined in Scheme 2. In Scheme 2, "P" designates an amine protectinggroup as defined herein. ##STR48##

As shown in Scheme 2 above, the polymeric hydroxylamine resin compoundis protected with an amine protecting group to form the N-protectedpolymeric hydroxylamine resin compound 6. The N-protected polymerichydroxylamine resin compound 6 is then alkylated as described in Scheme1 above to form the N-alkylated N-protected polymeric hydroxylamineresin compound 7. Removal of the amine protecting group provides themono N-alkylated polymeric hydroxylamine resin compound 8. Coupling of 8with a carboxylic acid compound of formula R_(a) CO₂ H as describedabove provides the polymeric N-alkylated hydroxamic acid resin compound3, which is converted to ketone 4 or aldehyde 5 as described in Scheme 1above.

Preferred amine protecting groups "P" include allyloxycarbonyl (Aloc),benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl (Moz),p-nitrobenzyloxycarbonyl (4-NO₂ --Z), trimethylsilylethoxycarbonyl(Teoc), 2,4-dim ethoxybenzyloxycarboiiyl, o-nitrobenzyloxycarbonyl,o-nitrobenzylsulfonyl (o-Nbs), p-nitrobenzylsulfonyl (p-Nbs), and2-nitro-4-trifluoromethylbenzenesulfonyl.

The most preferred amine protecting group is allyloxycarbonyl.

In a preferred aspect of the processes described in Schemes 1 and 2above, R_(a) represents the residual, non-carboxyl portion of a naturalor unnatural amino acid or peptide. Accordingly, the foregoing processespresent a facile route to the heretofore difficult to obtain amino acidor peptide aldehyde compounds.

In a process for preparing amino acid aldehyde or peptide amino acidsaccording to this invention, the N-terminal nitrogen atom of the aminoacid or peptide starting material is preferably protected with asuitable amine protecting group, designated herein as P". Furthermore,any functional groups contained in the amino acid or peptide sidechain(s) may be suitably protected to prevent interference with thereactions described herein.

In a preferred aspect of the preparation of amino acid or peptidealdehydes described above, P_(b) is benzyl or substituted benzyl.

In a more preferred aspect of the preparation of amino acid or peptidealdehydes described above, R_(b) is benzyl or benzyl substituted withhalogen, haloalkyl or alkoxy and P" is t-butyloxycarbonyl (BOC).

In addition, the N-alkylated hydroxamic acid resin compound 3 in whichR_(b) is the residual non-carboxyl portion of a natural amino acid orpeptide are amino acid or peptide aldehyde equivalents which may bestored and used to generate the corresponding amino acid or peptidealdehyde as needed by treatment with a hydride reducing agent and acidhydrolysis as described above.

Preferred polymeric N-protected hydroxylamine resin compounds includeN-allyloxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin,N-allyloxycarbonyl-4-[4-(O-methylhydroxylamine)-3-methoxyphenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%-divinylbenzene)-resin,N-allyloxycarbonyl-4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin,N-allyloxycarbonyl-4-[4-(1-aminoxyethyl)-2-methoxy-5-nitrophenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%divinylbenzene) resin,N-allyloxycarbonyl-O-hydroxylamine-2'-chlorotrityl-copolystyrene-1%-divinylbenzene-resin,N-allyloxycarbonyl-O-hydroxylamine-trityl-copolystyrene-1%-divinylbenzene-resin,N-allyloxycarbonyl-5-(4-O-methylhydroxylamine-3,5-dimethoxyphenoxy)-valericacid-copolystyrene-1%-divinyl benzene resin,N-allyloxycarbonyl-4-O-methylhydroxylamine-3-methoxyphenoxy-copolystyrene-1%-divinylbenzene resin,N-allyloxycarbonyl-4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin,N-allyloxycarbonyl-4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin andN-allyloxycarbonyl-3-hydroxy-xanthydrolamine-copolystryene-1%-divinylbenzeneresin.

The most preferred polymeric N-protected hydroxylamine resin compound isN-allyloxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin.

A process for the preparation of amines according to this invention isoutlined in Scheme 3. In Scheme 3, R_(d) and R_(e) independentlyrepresent H or any aliphatic or aromatic group amenable to the solventsand reagents utilized in the processes described herein, provided thatR_(d) and R_(e) are not both H.

The groups R_(a), R_(b) and R_(e) may be further substituted and maycontain functional groups suitable for further chemical transformationswhile attached to the hydroxylamine resin. It is understood that whenthese functional groups possess reactivity such that they couldpotentially interfere with the reactions described below, suchfunctional groups should be suitably protected. For a comprehensivetreatise on the protection and deprotection of common functional groupssee T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 2nd edition, John Wiley & Sons, New York (1991), incorporatedherein by reference. Rf represents any aliphatic or aromatic group whichis amenable for use as an organometallic reagent. ##STR49##

According to the foregoing Scheme 3, reaction of the polymerichydroxylamine resin compound 1 with an aldehyde or ketone 9 provides thepolymeric oxime ether resin compound 10. Oxime formation is preferablyaccomplished at about ambient temperature by swelling the polymerichydroxylamine resin compound 1 in a suitable inert organic solvent suchas dichloromethane, followed by addition of an excess of aldehyde orketone. Reductive cleavage of the resin, for example by reaction withNaCNBH₃, or BH₃ THF, followed by LiAlH₄ provides the amine 11. Reactionof the polymeric oxime ether resin compound 10 with an organometallicreagent of formula R_(f) M, wherein R_(f) is an aliphatic or aromaticanion and M is a metal cation as defined herein, provides the polymericα-substituted hydroxylamine resin compound 12. Cleavage of the α-amine13 from the resin, is accomplished, for example, using BH₃ -THF orLiAlH₄. See Y. Ukaji et al., Chem. Lett., 173, (1991) and R. P. Dieteret al., Can. J Chem. 71, 814 (1993). Preferred metal cations are Li andMgX wherein X is halogen. With the aid of a chiral auxiliary such as achiral benzyl hydroxyl amine linker, chiral α-substituted amines willresult.

A process for the preparation of lactones via radical cyclization isshown in Scheme 4. In Scheme 4, R_(g), R_(h) and R_(i) are aliphatic oraryl as defined herein. ##STR50## As shown in the foregoing Scheme 4,the polymeric hydroxylamine resin compound 1 is reacted with theα,βunsaturated carboxylic acid ester compound 14 to form the polymericoximyl resin compound 15. Radical cyclization of 15, for example byheating in the presence of 2,2'-azobisisobutyronitrile (AIBN) andthiophenol in an inert organic solvent such as benzene results information of the polymeric g-lactone resin compound 16. Acid hydrolysisof 16, using, for example 10% aqueous HCl, provides the lactone 17. SeeO. Miyata et al., Tet. Lett., 37, 229-232, (1996).

A process for the preparation of carbocyclic or heterocylic compounds byradical cyclization is shown in Scheme 5. In Scheme 5, R_(j), R_(k) andR_(i) are aliphatic or aryl as defined herein. The methodology describedin Scheme 1 is applicable to the preparation of 5-, 6- or 7-memberedrings. Carbocycles result when the phenolic oxygen atom is replaced witha carbon atom. ##STR51##

According to the foregoing Scheme 5, the polymeric hydroxylamine resincompound 1 is reacted with the acetophenone compound 18 and abromoalkene compound or o-bromobenzyl compound to form the polymericacetophenone oxime compounds 19 or 23. Radical cyclization of 19 or 23,for example by heating in the presence of AIBN and tri-n-butyltinhydride in an inert organic solvent such as benzene results in formationof the polymeric N-cyclyl hydroxylamine resin compounds 20 or 24.Treatment of 20 or 24 with acid, preferably trifluoroacetic acid,results in formation of the cyclic hydroxamic acid compounds 21 or 25.Reductive cleavage of 20 or 24, for example using LiAlH₄ as described inScheme 3 above, results in formation of the cyclic amine compounds 22 or26. See S. E. Booth et al., J. Chem. Soc. Commun., 1248-1249, (1991).

Hydroxamic acid compounds of formula 29, ##STR52## wherein Ar, A², R⁹,R¹⁰, R¹¹, R¹² and n are defined herein, are disclosed in WO 97/24117,incorporated herein by reference. Compounds of formula 29 inhibit theproduction or physiological effects of tumor necrosis factor (TNF) andare useful in treating a patient suffering from a pathological conditionsuch as inflammation or autoimmune disease characterized by aphysiologically detrimental excess of TNF.

A process for the preparation of a hydroxamic acid compound of formula29, wherein Ar, A², R⁹, R¹⁰, R¹¹, R¹² and n are as defined above,according to this invention is shown in Scheme 6. ##STR53## i)3-(4-methoxyphenylsulfonyl)propionic acid (5 equiv.);1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCl 5equiv.); DMF; 25° C.; 12 hours.

ii) 50% TFA in CH₂ Cl₂ (100 equiv.); 30 minutes.

According to the foregoing Scheme 6, the carboxylic acid compound 27 iscoupled to the polymeric hydroxylamine resin compound 1 as described inScheme 1 above to form the polymeric hydroxamic acid resin compound 28.The polymeric hydroxamic acid resin compound 28 is then be treated withan acid such as trifluoroacetic acid (TFA) in an inert solvent such asdichloromethane to liberate the hydroxamic acid compound 29. A higherpercentage of TFA (trifluoroacetic acid) and longer reaction times areneeded to cleave the hydroxamic acid from the Wang version compared tothe Rink version of the resin. During the evaporation of the TFA in thework-up to isolate the hydroxamic acid, it is found that heating thesample during concentration would generate a significant amount of theN,O-diacylated dimer of the parent hydroxamic acid as a side-product. Tominimize this side reaction the reaction mixture is concentrated at orbelow room temperature with toluene used as an azeotrope.

A process for the preparation of a polymeric α,β-unsaturated alkenoateresin compound 54 according to this invention is outlined in Scheme 7.In Scheme 7, R_(m) is H or aliphatic, R_(n) is aliphatic or aromatic,and R₂₀ and R₂, are alkyl. R_(m) and R_(n) may contain additionalfunctional groups. It is understood that these functional groups may besuitably protected to prevent interference with the reactions describedbelow. ##STR54##

According to the foregoing Scheme 7, coupling of the polymeric hydroxyresin 30 with the phosphono acetic acid compound 51 provides thepolymeric phosphonoacetoxy resin compound 31. The coupling is preferablyaccomplished using a preformed symmetric anhydride (method i below), orusing the 2,6-dichlorobenzoic acid anhydride described by Sieber, P.,Tetrahedron Lett., 1987, 28, 6147-6150 (method ii below).

i) 51 (6 equiv.); diisopropylcarbodiimide (3 equiv.); dichloromethane;0° C. 30 minutes, then 8,4-dimethylaminopyridine (0.2 equiv.); 12 hours.

ii) 51 (3 equiv.); 2,6-dichlorobenzoyl chloride (3 equiv.); pyridine (6equiv.); DMF; 12 hours.

The Homer-Emmons condensation of the polymeric phosphonoacetoxy resincompound 31 with the aldehyde R_(n) CHO is then accomplished by treating31 with an excess of a base such as potassium tert-butoxide, potassiumbis(trimethylsilyl)amide or lithium bis(trimethylsilyl)amide in anorganic solvent such as THF or toluene at about 0° C. to about 25° C.The mixture is stirred or shaken for a sufficient amount of time toquantitatively generate the resin-bound anion, generally from about 15minutes to about 2 hours. The aldehyde R_(n) CHO is then added and themixture is stirred for up to three days to generate the polymericalkenoate resin compound 32.

In an especially preferred preparation of the polymeric alkenoate resincompound 32, the polymeric phosphonoacetoxy resin compound 31 is treatedwith an excess of a base such as potassium tert-butoxide or lithiumbis(trimethylsilyl)amide in an organic solvent such as THF at about 0°C. to about 25° C. The mixture is stirred or shaken for a sufficientamount of time to quantitatively generate the resin-bound anion,generally from about 15 minutes to about 2 hours. The solvent and excessbase are then removed from the reaction vessel and a solution of thealdehyde in a less polar solvent mixture, comprising the solvent used inthe generation of the resin-bound anion and a second, less polarsolvent, is added at ambient temperature and the mixture is stirred forup to three days to generate the polymeric alkeneoate resin compound 32.

Preferred less polar solvents are alkanes such as pentane, hexane orheptane, or cycloalkanes such as cyclohexane, cyclopentane orcycloheptane. An especially preferred less polar solvent mixture is 60%cyclohexane-THF.

Use of the less polar solvent mixture in the Homer-Emmons condensationas described above presents a number of advantages over generation ofthe anion and condensation with the aldehyde using strong base in apolar solvent. A strong base is required to quantitatively generate theresin-bound anion. However, under the reaction conditions of strong baseand a relatively polar solvent, the resin linkage was hydrolyzedresulting in a low yield of the polymeric alkeneoate resin compound 32.However, draining the solvent and excess base following essentiallyquantitative generation of the resin-bound anion and adding a solutionof the aldehyde R_(n) CHO in a less polar solvent mixture appears tostabilize the resin linkage toward hydrolysis and thereby results inunexpectedly high yields of the polymeric alkeneoate resin compound 32.

The polymeric alkeneoate resin compound 32 may be used for furthertransformations as described in Scheme 8, or the α,β-unsaturated acidcompound 54 may be cleaved from the resin using methods commonly knownin the art, for example by treating a mixture of the polymericalkeneoate resin compound 53 in a suitable organic solvent such asdichloromethane, dichloroethane or dioxane, with acid. Cleavage ispreferably accomplished at about ambient temperature using atrifluoroacetic acid (TFA)-dichloromethane solvent mixture over about 1hour.

A process for the solid phase synthesis of the carboxylic acid compound27 an intermediate useful for preparing the hydroxamic acid compound 29in which Ar, A², n and R¹¹ are as defined herein and R⁹, R¹⁰ and R¹² areH, is shown in Scheme 8. ##STR55##

The polymeric diethylphosphonoacetoxy-resin compound 31 is treated witha base such as potassium bis (trimethylsilyl) amide in an inert solventsuch as toluene, at a temperature of about 0° C., followed by analdehyde of formula R¹¹ CHO wherein R¹¹ is as defined above, at aboutambient temperature to give the polymeric alkenoate resin compound 32.

According to the foregoing Scheme 8, reaction of the polymeric alkenoateresin compound 32a, prepared as described in Scheme 7, with a thiol offormula Ar--A² --SH, wherein Ar and A² are as defined above, providesthe polymeric alkanoate resin compound 33. The addition may beconveniently carried out under mild basic conditions, for example in thepresence of lithium hydroxide at about ambient temperature.

The polymeric alkanoate resin compound 33 may then be hydrolyiticallycleaved by treatment with acid as described in Scheme 7, above, toprepare the carboxylic acid compound 27 wherein n is 0.

Alternatively, the polymeric alkanoate resin compound 33 may be treatedwith an oxidizing agent such as ti-chloro-perbenzoic acid in an inertsolvent such as dioxane at about ambient temperature to give thepolymeric sulfoxide (n=1) or sulfone (n=2) resin compound 34. Acidhydrolysis of 34 as described in Scheme 7, above, provides thecarboxylic acid compound 35.

The preparation of the polymeric hydroxylamine resin compound 1 isoutlined in Scheme 9a. ##STR56##

According to the foregoing Scheme 9a, a polymeric hydroxy resin compound30 is converted to the polymeric N-hydroxylphthalimido resin compound 36by coupling with N-hydroxyphthalimide under Mitsunobu conditions(Mitsunobu, O., Synthesis 1981, 1), by conversion of the hydroxy groupto a leaving group such as the mesylate followed by nucleophilicdisplacement, or by reaction of the polymeric hydroxy resin compoundwith N-hydroxyphthalimide in the presence of an acid such asbenzenesulfonic acid. Removal of the phthalimido group provides thepolymeric hydroxylamine resin compound 1.

For example, when 30 is4-(hydroxymethyl)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(Wang resin), N-hydroxyphthalimide is coupled to the resin in thepresence of diisopropylazodicarboxylate and triphenylphosphine in DMF.The phthalimido protection is removed by methylaminolysis in THF at 40°C. The reaction is complete in about 2 hours. The use of the methylamineto cleave the phthalimide protection offers a significant advantage overthe commonly used hydrazinolysis procedure (Wolf et al., Can. J. Chem.,1970, 48, 3572.

When4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(Rink resin) is utilized 1 is preferably prepared by reaction of thepolymeric hydroxy resin compound with N-Hydroxy phthalimide in DMF inthe presence of catalytic benzene sulfonic acid to form the polymericN-hydroxyphthalimido resin compound 36. The phthalimido protecting groupis then removed by reaction with hydrazine hydrate in tert-butanol atabout 60° C. to give the corresponding polymeric hydroxylamine resincompound.

An alternative route to the polymeric N-protected hydroxylamine resin 6is outlined in Scheme ##STR57##

According to the foregoing Scheme 9, a polymeric hydroxy resin compound30 is coupled with a N,N-diprotected hydroxylamine compound 37, whereinP and P' are amine protecting groups as described in Scheme 8 above toform the polymeric N,N-diprotected hydroxylamine resin compound 38. Theamine protecting group P' is then selectively removed to form thepolymeric N-protected hydroxylamine resin compound 6.

In a preferred embodiment of the synthesis described in Scheme 9, P isbenzyl and P' is allyloxycarbonyl. Selective removal of theallyloxycarbonyl protecting group is effected by treatment withtetrakis(triphenylphosphine)Palladium(0).

The N,N-diprotected hydroxylamine compound 37 is prepared by sequentialintroduction of the protecting groups P and P' to an O-protectedhydroxylamine compound of formula H₂ NOP² wherein P² is a hydroxyprotecting group. A preferred hydroxy protecting group is alkyl. Theamine protecting groups P and P' are then introduced using reagents andreaction conditions well known in the art of organic synthesis. ForExample, reaction of O-tert-butylhydroxylamine withallyloxychloroformate results in formation ofN-allyloxycarbonyl-O-tert-butylhydroxylamine, which is then reacted withbenzyl bromide to formN-benzyl-N-allyloxycarbonyl-O-tert-butylhydroxylamine. Treatment ofN-benzyl-N-allyloxycarbonyl-O-tert-butylhydroxylamine withtrifluoroacetic acid gives N-benzyl-N-allyloxycarbonylhydroxylamine.

The preparation of a polymeric4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl resincompound is shown in Scheme 10. ##STR58##

According to the foregoing Scheme 10, a polymeric chloromethyl resincompound such as chloromethyl polystyrene (39, Merrifield resin) isreacted with 4-hydroxy-2,3,5,6-benzoic acid in the presence of base toform the ⁴ -carboxy-2,3,5,6-tetrafluorophenoxymethyl resin compound 40.Reduction of the carboxylic acid group, for example using LiAlH₄,diisobutylaluminum hydride, or BH₃ -THF provides the ⁴-hydroxymethyl-2,3,5,6-tetrafluorophenoxymethyl resin compound 41.Conversion of 41 to the hydroxyphthalimido resin compound 42, followedby removal of the phthalimido group as described in Scheme 8 aboveprovides the4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin compound 43.

The preparation of a polymeric4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethylresin compound is shown in Scheme 11. ##STR59##

According to the foregoing Scheme 11, a polymeric chloromethyl resincompound is reacted with 4-phenoxy-2,3-5,6-tetrafluorophenyl2,4-dimethoxyphenyl ketone 44 in the presence of base as described inScheme 10 above to form the4-(2',4'-dimethoxyphenylcarbonyl)-2,3,5,6-tetrafluorophenoxymethyl-resincompound 45. Reduction of the carbonyl, for example using LiBH4,provides the4-(hydroxymethyl-2',4'-dimethoxyphenyl)-2,3,5,6-tetrafluorophenoxymethyl resin compound 46. Conversion of 46 to the hydroxyphthalimidoresin compound 47, followed by removal of the phthalimido group asdescribed in Scheme 8 above provides the4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-resin compound 48.

Preferred polymeric hydroxylamine resin compounds have formula 1 whereinL is a linking group.

Preferred linking groups L have the formula ##STR60## wherein A isabsent or a group of formula --X¹ --Z-- wherein

X¹ is --CHR-- or --CHR--Y--CO--(CH₂)_(n) -- wherein R is H, alkyl,phenyl, or phenyl substituted with --H, alkyl, alkoxy, halogen, nitrileor --NO₂,

Y is --O-- or --NH--;

n is an integer from 1 to 6, and

Z is --O-- or --NH--;

R¹, R^(1a), R², and R^(2a) are independently --H, alkyl, alkoxy,halogen, nitrile or --NO₂ ; and

R³ and R⁴ are independently --H, alkyl, phenyl, or phenyl substitutedwith one or more substituents selected from alkyl, alkoxy, halogennitrile and --NO₂ ;

or one of R¹ and R² taken together with one of R³ and R⁴ and the carbonatoms to which they are attached define a linking group of formula##STR61## wherein R¹ is --H, alkyl, alkoxy, halogen, nitrile or --NO₂ ;and

R⁶, R⁷ and R⁸ are independently selected from --H, alkyl, alkoxy,halogen, nitrile or --NO₂.

More preferred linking groups have formula ##STR62## wherein R¹ and R²are independently H or F; R^(1a) and R^(2a) are simultaneously H or F;and

one of R³ and R⁴ is H and the other is H or 2,4-dimethoxyphenyl.

Representative preferred polymeric hydroxslamine resin compounds include4-(O-methylhiydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin, designated herein ##STR63##4-[4-(O-methylhydroxylamine)-3-methoxyphenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%-divinylbenzene)-resin,designated herein as ##STR64##4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin, designated herein as ##STR65##4-[4-(1-aminoxyethyl)-2-methoxy-5-nitrophenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%divinylbenzene) resin, designated herein as ##STR66##O-hydroxylamine-2'-chlorotrityl-copolystyrene-1%-divinylbenzene-resin,designated herein as ##STR67##O-hydroxylamine-trityl-copolystyrene-1%-divinylbenzene-resin, designatedherein as ##STR68## 5-(4-O-methylhydroxylamine-3,5-dimethoxyphenoxy)-valeric acid-copolystyrene-1%-divinyl benzeneresin, designated herein as ##STR69## 4-O-methylhydroxylamine-3-methoxyphenoxy-copolystyrene-1%-divinyl benzeneresin, designated herein as ##STR70##

3-hydroxy-xanthydroxylamine-copolystryene-1%-divinylbenzene resin,designated herein as ##STR71##4-(O-methylhydroxylamine)-2.3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin, designated herein as ##STR72##4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin, designated herein as ##STR73##

The most preferred polymeric hydroxylamine resin compounds are

4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenloxymethyl-copoly(styrene-1%divinylbenzene) resin,

4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin,

4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene)resin, and

4-(2',4'-dimethoxypbenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin.

The Rink handle (H. Rink, Tet. Lett., 28, 3787-3790, 1987) has theadvantage of being cleaved under mild acidolysis for short periods oftime (i.e. 10% TFA in DCM for 10-15 minutes.). However, due to the costof the resin it is desirable to synthesize the corresponding functionalresin on the Wang solid support ((a) S. S. Wang, J. Am. Chem. Soc.,1973, 95, 1328. b) Lu et al., J. Org. Chem., 1981, 46, 3433).

The polymeric hydroxylamine resin compounds in which R_(1a) and R_(1b)are F are especially useful as it lends itself to ready quantificationof resin loading and monitoring of reactions conducted on the resinusing fluorine NMR.

The methods described herein are also useful for the preparation ofpeptide aldehydes, ketones and hydroxamic acids. In general, this methodinvolves coupling the carboxyl group of a suitably N-protected firstamino acid to the resin to form the polymeric N-protected amino acidhydroxamic acid resin compound. The amino acid N-protecting group isthen removed and the unprotected polymeric amino acid hydroxamic acidresin compound is coupled with a second suitably N-protected amino acid.This process is then repeated until the desired amino acid residues havebeen incorporated in the peptide.

Alternatively, peptides comprising multiple amino acids are prepared bycoupling a suitably N-protected peptide subunit comprising two or moreamino acids to form the polymeric N-protected peptide hydroxamic acidresin compound. The amino acid N-protecting group is then removed andthe unprotected polymeric peptide hydroxamic acid resin compound iscoupled with a second suitably N-protected amino acid or peptide. Thus,in addition to the sequential addition of individual amino acid subunitsdescribed above, a polypeptide may be prepared by coupling of peptidesubunits.

Once the desired amino acids have been incorporated into the peptide,the polymeric peptide hydroxamic acid compound is reacted with anorganometallic reagent followed by acid hydrolysis to form the peptideketone compound; reductively cleaved to form the peptide aldehydecompound; or cleaved with acid to form the peptide hydroxamic acidcompound. Any remaining protecting groups may be removed prior to orsubsequently to cleavage of the peptide from the resin.

N-protecting groups suitable for use in peptide synthesis as describedherein should have the properties of being stable to the conditions ofcoupling to the polymeric hydroxylamine resin compound while beingreadily removable without destruction of the growing peptide chain orracemization of any of the chiral centers contained therein. Suitableprotecting groups are 9-fluorenylmethyloxycarbonyl (Fmoc),t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),biphenylisopropyloxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl,(a,a)dimethyl-3,5-dimethoxybenzyloxycarbonyl, o-nitrophenylsulfenyl,2-cyano-t-butyloxycarbonyl, and the like.

Additionally, this resin is useful for constructing arrays of aldehyde,ketone or amine combinatorial libraries or arrays of aldehydes andketones as reagents in combinatorial library synthesis, for examplereagents for the Ugi 4-component condensation (Ivar Ugi, in IsonitrileChemistry, 1971, p. 145, Academic Press). The hydroxylamine bound resinmay be used not only for single functional group transformations, butalso multiple step solid phase synthesis to generate combinatoriallibraries.

The functionalized resin of this invention is also useful for theparallel synthesis of a multiplicity of different aldehyde, ketone oramine end products as outlined for ketone compounds in Schemes 12a and12b. In Schemes 12a and 12b, R_(b) and R_(c) are as defined above. n isan integer which represents the total number of different aldehyde,ketone or amine products which are to be prepared. R_(a1) --R_(an)represent, independently, an aliphatic or aromatic group as definedherein. ##STR74##

The parallel synthesis of a multiplicity of ketone compounds using amultiplicity of carboxylic acid compound R_(a1) CO₂ H--R_(an) CO₂ H anda single organometallic compounds R_(c) MgX is shown in Scheme 12a.According to Scheme 12a, the N-alkylated hydroxylamine resin compound 8,prepared as described in Scheme 2, is divided into n portions. Eachportion of resin is then coupled with a different carboxylic acidcompound to give n portions of polymeric N-alkylated hydroxamic acidresin compound. Each portion of polymeric N-alkylated hydroxamic acidresin compound is then reacted with a Grignard reagent of formula R_(c)X and subjected to acid hydrolysis to give n portions of ketone derivedfrom a single organometallic reagent. ##STR75##

The parallel synthesis of n different ketone compounds derived from asingle carboxylic acid compound R_(a) CO₂ H and n differentorganometallic compounds R_(c1) MgBr to R_(cn) MgBr is outlined inScheme 12b above. According to Scheme 12b, the polymeric N-alkylatedhydroxylamine resin compound is coupled with a carboxylic acid offormula R_(a) CO₂ H. The resulting polymeric N-alkylated hydroxamic acidresin compound is then divided into n portions, and each portion ofpolymeric N-alkylated hydroxamic acid resin compound is then reactedwith a different Grignard reagent R_(c1) --R_(cn) MgBr and subjected toacid hydrolysis to give n different ketone compounds derived from asingle carboxylic acid compound.

The functionalized resins of this invention are also useful forconstructing a combinatorial library of ketones or amines as illustratedfor the ketone library derived from 4 carboxylic acid compounds and 4Grignard reagents as outlined in Scheme 13. ##STR76##

According to the foregoing Scheme 13, the polymeric N-alkylatedhydroxylamine resin compound 8 is divided in 4-portions, and eachportion is coupled with a different carboxylic acid compound to prepare4 different polymeric N-alkylated hydroxamic acid resin compounds. The 4portions of polymeric N-alkylated hydroxamic acid resin compounds arethen mixed together to form a single portion which is then divided into4 portions of polymeric N-alkylated hydroxamic acid resin compounds, inwhich each portion contains approximately equal amounts of eachindividual polymeric N-alkylated hydroxamic acid resin compound. Each ofthe 4 portions is then reacted with a different Grignard reagent R_(c1)--R_(c4) MgBr and subjected to acid hydrolysis to give 4 portions ofketone compound, each of which contains 4 compounds representing theproducts of reaction of each of the 4 different polymeric N-alkylatedhydroxamic acid resin compounds with a single Grignard reagent. In thismanner a combinatorial library containing a multiplicity of ketonecompounds may be quickly constructed.

In a similar manner, a combinatorial library of peptides may beassembled by repeating the dividing-recombining sequence for each aminoacid or peptide building block.

The foregoing may be better understood by reference to the followingExamples, which are presented for illustration and not intended to limitthe scope of the invention.

EXAMPLE 1

4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin. ##STR77##

Rink acid resin (1 g; 0.63 mmol) is swelled in DMF (10 mL) for 15minutes at ambient temperature. N-Hydroxyphthalimide (514 mg; 3.15 mmol)is added to the resin suspension followed by benzene sulfonic acid (19mg; 0.13 mmol). The mixture is stirred by means of a mechanical stirrerand heated to 50° C. for five hours. The mixture is then cooled toambient temperature and stirred for an additional 12 hours, after whichthe resin is filtered and washed extensively with DMF (5×25 mL); DMF:H₂O (70:30; 5×25 mL); THF (10×25 mL); and diethyl ether (10×25 mL). Theresin is then dried overnight under high vacuum at 40° C. The IRspectrum shows a carbonyl absorbance at 1733 cm⁻¹ corresponding to thephthalimido carbonyl stretch. Elemental analysis: calcd.:0.28%N. Found:0.26%N. Loading=0.18 mmol/g.

The resin is swelled in 20 mL of tert-butanol for ten minutes. Hydrazinehydrate (10 mL) is added to the mixture and the reaction is warmed to60° C. with mechanical stirring for 12 hours. After which the reactionis cooled to ambient temperature. The resin is filtered and washedextensively with DMF (10×25 mL), THF (10×25 mL), and diethyl ether(10×25 mL), then dried under high vacuum at 40° C. overnight. The IRspectrum of resin III showed the loss of the carbonyl stretch at 1733cm⁻¹ which is present in the starting material. Elemental Analysis: %Nfound=0.43; 0.42 (corresponding to a loading level of 0.3 mmol/g).

EXAMPLE 2

N-[3-((4-methoxyphenyl)sulfonyl)prop-1-ylcarbonyl]4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin. ##STR78##

4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin (200 mg) is swelled in DMF (3 mL). To thissuspension is added 3-(4-methoxyphenylsulfonyl)propionic acid (610 mg;2.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (EDCl; 477 mg; 2.5 mmol) at ambient temperature. Thereaction mixture is shaken at ambient temperature using a vortex shakerfor 12 h, after which the resin is filtered and washed extensively withDMF:H₂ O (80:20; 5×5 mL), DMF (5×5 mL), THF (5×5 mL), and diethyl ether(5×5 mL). The resin IV is dried under high vacuum at 40° C. for 12hours. The IR spectrum shows a carbonyl absorbance at 1675 cm⁻¹corresponding to the bound hydroxamate.

EXAMPLE 3

N-hydroxy-3-(4-methoxyphenylsulfonyl)propionamide.

DryN-[3-((4-methoxyphenyl)sulfonyl)prop-1-ylcarbonyl]4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin (200 mg), prepared as in Example 2, is swelled in3 mL of methylene chloride for 10 minutes. Trifluoroacetic acid (TFA;0.3 mL) is added to the mixture dropwise at ambient temperature and theresulting mixture is vortexed for 30 minutes. The resin turned a darkblue upon addition of the TFA. The mixture is then filtered and washedwith two 5 mL portions of methylene chloride. The filtrate is evaporatedby rotary evaporation to yield 20 mg of crude product. An LC/MS trace ofthe crude reaction mixture showed it to contain better than 75 area % ofthe desired product, 3-(4-methoxyphenylsulfonyl)propionic acid ispresent in 6 area %). ¹ H NMR (MeOH-d₄) δ 2.45 (t,2H); 3.45 (t,2H); 3.90(s,3H), 7.15 (d, 2H); 7.85 (d, 2H).

EXAMPLE 4

4-O-Methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(100-200 mesh). ##STR79##

A 1-L jacketed reactor with a bottom valve and overhead stirrer (Acecatalog #8090) is charged with Wang resin (18.35 g, 20 meq) andanhydrous tetrahydrofuran (THF. 450 mL). This mixture is stirred gentlyfor about 15 minutes, then as much solvent as possible is removedthrough a tube fitted with a porous glass frit via vacuum aspiration.Fresh THF is added, followed by triphenylphosphine (15.74 g, 60 mmol)and N-Hydroxyphthalimide (16.31 g, 100 mmol). The resulting mixture isstirred and cooled to -5-0° C. Diisopropyl azodicarboxylate (11.8 mL, 60mmol) is added slowly so as to maintain the temperature at <5° C. Whenthe addition is complete, the stirred mixture is allowed to warm slowlyto room temperature and stirred overnight. As much of the reactionliquors as possible is removed by aspiration through the dip tube asabove. The resin is washed by charging N,N-dimethylformamide (DMF, 200mL), stirring the mixture for 3-5 minutes, and then removing byaspiration as much of the wash solution as possible. Similarly, theresin is washed sequentially with an additional portion of DMF andportions of methanol (twice), THF (twice), and methanol (once). Aportion of the resin may be removed for analysis: IR 1734 cm⁻¹ (C═O).

To the resin remaining in the reactor is added THF (400 mL) and 200 mLof a 40% aqueous solution of methylamine (2.31 mol). This reactionmixture is stirred gently at 40° C. for 2 hours, then cooled to roomtemperature (the mixture may be held overnight at this temperature). Asmuch of the reaction liquor as possible is removed by aspiration, andthe resin is washed with the solvent array as above. Following the finalmethanol wash, additional methanol is used to flush the resin out of thebottom of the reactor and isolate it by filtration. The filtered resinis dried at 40° C. under vacuum. Yield 18-18.5 g resin: amine load 1.02meq/g (based on potentiometric titration of a THF suspension withp-toluenesulfonic acid); IR (microscopy) 3316 cm⁻¹ (w, --NH₂). Analysisfound C, 87.07%; H. 7.77%; N, 1.58%, which corresponds to 1.13 nitrogenatoms/g resin.

Assay: preparation of 4-nitrophenylethanehydroxamic acid.

A 200 mg sample of the dried resin (ca. 0.2 mmol) is charged to a 5- or10-mL resin reactor (a polypropylene syringe barrel fitted with apolypropylene frit). The resin is swelled for about 15 minutes in dryDMF, and then 115 mg /1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCl, 0.6 mmol) is added. To this mixture is then added4-nitrophenylacetic acid (115 mg, 0.6 mmol). The reactor is capped andthe mixture is agitated slowly overnight (a rocker bed apparatus isused). The reaction liquors are removed by vacuum filtration (the resinreactor is inserted through a small rubber vacuum flask adapter), andthe resin is washed by several small (2-3 mL) portions of the followingsolvents: DMF (4-5 portions), MeOH or 50% aq. DMF (3-4 portions), THF(3-4 portions), and MeOH (2-3 portions). The resin (still in the syringereactor) is dried for at least 4 hours under vacuum at 40° C.

To this dried resin is added 2 mL dichloromethane followed by 2 mLtrifluoroacetic acid (TFA). Additionally, 20 mL water is added (believedto reduce "anhydride" formation from hydroxamic acid product). Themixture is allowed to react for about 1 hr, and the reaction liquors aredrained into a tared collector. The resin is washed with 1-2 1-mLportions of dichloromethane followed by 1-2 1-mL portions of toluene.The combined filtrates are concentrated to about 2 mL at 30° C., 2 mLadditional toluene is added, and the resulting solution is concentratedto dryness under vacuum (rotary evaporator followed by vacuum oven at30° C.; note that heating in the presence of TFA promotes formation ofthe "anhydride" impurity). The residue is weighed and analyzed forweight % purity (HPLC, using the carboxylic acid as a response factorstandard). Typical results for 4-nitrophenylethanehydroxamic acid: 29-30mg solids at 60-70 wt % purity, 90-97 A % purity (261 nm); ¹ H NMR (CD₃OD) δ 8.13 (d, 2H), 7.25 (d, 2H), 4.85 (bs, OH, NH), 3.55 (s, 2H); ¹³ CNMR δ 169.4, 144.3, 131.3, 124.6, 40.2. This reflects a load/clipchemical yield of 50-55% from resin at 1 meq/g.

EXAMPLE 5

N-4-phenylbut-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR80##

Dry4-O-Methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(2 g, 1.5 mmol), prepared as in Example 4, is allowed to swell in DMF (8mL) for 10 minutes and then is treated with 4-phenyl butyric acid andEDC (0.86 g, 4.5 mmol). The mixture is shaken for 24 hours and filtered.The resin is washed with DMF, DMF/H₂ O, DMF, THF and Et₂ O and driedunder vacuum at 40° C. to giveN-4-phenylbut-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(2.2 g). IR: C═O 1670 cm⁻¹. Elemental analysis: calcd; N, 1.05%. Found:N, 1.07%.

EXAMPLE 6

N-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR81##

Dry4-O-Methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(4 g, 3 mmol), prepared as in Example 4, is allowed to swell in DMF (32mL) for 10 minutes, then is treated with 4-bromo-3-methylbenizoic acidand EDC (1.725 g, 9 mmol). The mixture is shaken for 24 hours andfiltered. The resin is washed with DMF, DMF/H₂ O, DMF, THF and Et₂ O anddried under vacuum at 40° C. to giveN-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(4.5 g). IR: C═O 1677.5cm⁻¹. Elemental analysis: calcd: Br, 5.2%; N,1.05%. Found: Br, 5.3%; N, 0.91%.

EXAMPLE 7

N-Hydroxy-4-bromo-3-methyl benzamide.

N-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1-divinylbenzene)-resin,prepared as in Example 6, is suspended in 50% TFA/CH₂ Cl₂ for 2 hours.The resin is filtered and washed three times with CH₂ Cl₂ to giveN-Hydroxy-4-bromo-3-methyl benzamide. LC MS: m/z 230/232 (Br)[M+H]⁺Area=78%; ¹ H NMR (300 MHz, CDCl₃) δ: 2.42 (s, 3 H), 7.4 (bd J=7.89, 1H)7.58 (bd J=7.89 1H), 7.62 (bs, 1H).

EXAMPLE 8

N-4-bromobenzyl-N-4-phenylbut-1-ylcarbonyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR82##

N-4-phenylbut-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(1.46 g, 1.095 mmol), prepared as in Example 5, is suspended in toluene(26 mL) for 10 minutes. DBU (0.83 mL; 5.5 mmol) is added and the mixtureis agitated for 2 hours on a wrist shaker. Bromobenzyl bromide (4.1 g,16.425 mmol) is added and the reaction mixture is vigorously agitatedfor 4 days. The resin is filtered and washed with DMF, DMF/H₂ O, DMF,THF and Et₂ O and dried under vacuum at 40° C. to giveN-4-bromobenzyl-N-4-phelnylbut-1-ylcarbonyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(1.4 g). IR C═O 1668 cm⁻¹. Elemental Analysis: calcd: Br, 5.3%; N,0.94%. Found: Br, 5.4%; N, 0.85%.

EXAMPLE 9

4-Phenyl butyraldehyde.

N-4-bromobenzyl-N-4-phenylbut-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(0.2 g, 0.6 mmol/g 0.12 mmol) is suspended in diethyl ether for 10minutes and then cooled to 5° C. in an orbital shaker. The suspension istreated with LiAlH₃ OMe (0.46 M in diethyl ether, 0.22 mL, 0.1 mmol) andagitated for 30 minutes at this temperature. The reaction mixture isquenched by the addition of 2 M HCl (aq) and vortexed for 30 minutes.Sodium potassium tartrate is added and the mixture vortexed for afurther 10 minutes. Sodium sulfate is added and the mixture is filteredthrough a plug of silica gel, washing thoroughly with dichloromethane.The filtrate is concentrated to give 4-phenyl butyraldehyde. GC:Area=91%; ¹ H NMR (CDCl₃) δ 9.75 (1H,s), 7.05-7.30 (5H,m), 2,58-2.68(2H,m), 2.41-2.50 (2H,t), 1.91-2.02 (2H,m): MS (EI): m/z=149 [M+H⁺ ].

EXAMPLE 10

6-Phenylhexan-3-one.

N-4-bromobenzyl-N-4-phenylbut-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(0.15 g, approx. 0.75 mmol/g 0.11 mmol) is suspended in diethyl ether (1mL) and treated with 1 M solution of ethyl magnesium bromide intetrahydrofuran (0.34 mL, 0.34 mmol). The reaction mixture is agitatedfor 18 hours, and then quenched by the addition of 2 M HCl (aq) (approx.pH 3 is obtained). The mixture is agitated for 30 minutes. Sodiumsulfate is added and the mixture is filtered through a plug of silicagel, washed thoroughly with dichloromethane and concentrated to give of6-phenylhexan-3-one. GC MS (EI) Area=97.1%, m/z 176.2 (M)⁺ ; MS (EI-LRP)m/z 176 (M)⁺ ; NMR (300 MHz, CDCl₃) δ 1.02 (t, 3H), 1.9 (m, 2H), 2.4 (m,4H) 2.6 (m, 2H), 7.2-7.3 (m, 5H).

EXAMPLE 11

N-4-chlorobenzyl-N-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR83##

N-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(2.8 g, 2.1 mmol), prepared as in Example 6, is suspended in toluene (27mL) and the mixture is stirred for 10 minutes. DBU (1.6 go 10.5 mmol) isadded and the mixture is agitated for 2 hours on a wrist shaker.Chlorobenzyl bromide (6.47 g, 31.5 mmol) is added and the reactionmixture is vigorously agitated for 3 days. The resin is filtered andwashed with DMF, DMF/H₂ O, DMF, THF and Et₂ O, and dried under vacuum at40° C. to giveN-4-chlorobenzyl-N-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(3 g). IR C═O 1644 cm⁻¹, Elemental Analysis: calcd: Br, 4.2%; Cl, 1.9%;N, 0.8%. Found: Br, 3.8%; Cl, 2.0%; N, 0.9%.

EXAMPLE 12

N-(4-Chlorobenzyl)-N-hydroxy-3-methyl-4-bromobenzamide.

N-4-chlorobenzyl-N-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin,prepared as in Example 11, is suspendedin 50% TFA/CH₂ Cl₂ for 2 hours.The resin is filtered and washed three times with CH₂ Cl₂ to giveN-(4-Chlorobenzyl)-N-hydroxy-3-methyl-4-bromobenzamide. LC MS (H-ISP)m/z 354/356 (Cl/Br) [M+H⁺ ]. Area 64%; ¹ H NMR (300 MHz, CDCl₃) δ 2.3(bs, 3H), 4.65 (bs, 2H), 7.2-7.6 (m, 7H).

EXAMPLE 13

4-Bromo-3-methyl benzaldehyde.

N-4-chlorobenzyl-N-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(0.2 g, 0.5 mmol/g 0.1 mmol), prepared as in Example 11, is suspended indiethyl ether for 10 minutes and then cooled to 5° C. in an orbitalshaker. The suspension is treated with LiAlH₃ OMe (0.46 M in diethylether, 0.2 mL, 0.092 mmol) and agitated for 30 minutes at thistemperature. The reaction mixture is quenched by the addition of aqueous2 M HCl and vortexed for 30 minutes. Sodium potassium tartrate is addedand the mixture is vortexed for a further 10 minutes. Sodium sulfate isadded and the mixture is filtered through a plug of silica gel, washingthoroughly with dichloromethane. The filtrate is concentrated to give4-bromo-3-methyl benzaldelhyde. GC MS: EI Area=99.5%, m/z 179/199(Br)[M]⁺ ; ¹ H NMR (CDCl₃) δ 9.94 (1H,s), 7.70 (2H,d), 7.52 (1H,d), 2.45(3H,s); MS (EI): m/z=199 [M+H]⁺.

EXAMPLE 14

1-(4-Bromo-3-methyl phenyl) propan-1-one.

N-4-chlorobenzyl-N-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(0.23 g, 0.5 mmol/g 0.115 mmol), prepared as in Example 11, is suspendedin diethyl ether (1 mL) and treated with ethyl magnesium bromide (1.0 Min THF, 0.23 mL, 0.23 mmol). The reaction mixture is agitated for 18hours, and then quenched by the addition of aqueous 2 M HCl (approx. pH3 is obtained). The mixture is agitated for 30 minutes. Sodium sulfateis added and the mixture is filtered through a plug of silica gel,washing thoroughly with dichloromethane. The residue is concentrated togive 1-(4-Bromo-3-methyl phenyl) propan-1-one. GC Area=78.7%; MS (EI)m/z 226 Br [M⁺ -H]; NMR (300 MHz, CDCl₃) δ 1.22 (t J=7.89, 3H), 2.96 (qJ=7.89, 2H), 7.6 (bs, 2H), 7.8(s, 1H).

EXAMPLE 15

N-3-bromobenzaldehydeoxime-4-O-Methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR84##

4-O-Methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(105 mg; 0.08 mmol) is swelled in dichloromethane (DCM)(@ mL) for 10minutes. Trimethylorthoformate (1 mL) and 3-bromo-benzaldehyde (500 mg;2.7 mmol; 34 equiv.) is added to the resin and the mixture is shakenovernight. The slurry is then filtered, rinsed with dichloromethane (5mL), DMF (5 mL×3), H₂ O (5 mL×4), THF (5 mL×10, and Et₂ O (5 mL×10). Theresin is dried in vacuo at 40° C. for 12 hours. IR oxime stretch 1602cm⁻¹. Elemental Analysis: calcd: Br, 5.52%; N, 1.04%. Found: Br, 5.76%;N, 1.08%.

EXAMPLE 16

N-3-(4-methoxphenyl)propan-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR85##

4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(1 g, 0.73 mmol) is allowed to swell in DMF for 10 minutes and then istreated with 3-(4-methoxyphenyl)propionic acid (0.658 g, 3.65 mmol) andDIC (0.46 g, 3.65 mmol). The mixture is shaken for 24 hours, thenfiltered and the residue is washed with DMF, DMF/H₂ O, DMF, THF and ET₂O, and dried under vacuum at 40° C. to giveN-3-(4-methoxphenyl)propan-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.IR: C═O 1698 cm⁻¹. Elemental Analysis: calcd: N, 1.02%. Found: N, 1.21%.

EXAMPLE 17

N-hydroxy-3-(4-methoxyphenyl)propionamide.

N-hydroxy-3-(4-methoxyphenyl)propionamide is prepared by reaction ofN-3-(4-methoxphenyl)propan-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinwith TFA using the procedure of Example 7. ¹ H NMR 300 MHz (CDCl₃, CD₃OD) δ 2.25 (t, 2H), 2.78 (t, 2H), 3.68 (s, 3H), 6.72 (d, 2H), 7.04 (d,2H).

EXAMPLE 18

N-2-(4-bromophenyl)ethan-1-oyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR86##

The title resin is prepared using the method of Example 16, exceptsubstituting 4-bromophenylacetic acid for 3-(4-methoxyphenyl)propionicacid. IR C═O 1713.9 cm⁻¹. Elemental analysis: calcd: Br, 5.8%; N, 1.02%.Found: Br, 8.29%, 8.18%; N, 0.97%, 0.96%.

    ______________________________________                                        EDS: Net X-ray Counts                                                                K line        L line  M line                                           ______________________________________                                        O:     969           1024                                                       C:          2662        3003                                                  Br:                                  12855 10436                            ______________________________________                                    

EXAMPLE 19

N-4-bromocinnamoyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR87##

The title resin is prepared using the method of Example 16, exceptsubstituting 4-bromocinnamic acid for 3-(4-methoxyphenyl)propionic acid.IR:C═O 1671.7 cm⁻¹ (broad). Elemental analysis: Calcd: Br, 5.8%, N,1.02%. Found: Br, 4.45%, 4.54%.

    ______________________________________                                        EDS: Net X-ray Count                                                                  K line        L line  M line                                          ______________________________________                                        O:      818           1365                                                      C:         4549         5059                                                  Br:                                  6384 5271                              ______________________________________                                    

EXAMPLE 20

N-hydroxy-4-bromocinnamamide.

N-hydroxy-4-bromocinnamamide is prepared by treatingN-4-bromocinnamoyl-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinwith TFA using the procedure of Example 7. LC MS (H-ISP) m/z 241/243 Br[M⁺ ], Area=84%; ¹ H NMR (300 MHz, CDCl₃ CD₃ OD) δ: 3.23 (s, 1H), 6.3 5(d, J=15.8), 7.3 (d, J--7.9), 7.4 (d, J=7.9), 7.6 (d, J=15.8).

EXAMPLE 21

N-(4-chlorobenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR88##

The title resin is prepared using the method of Example 16, exceptsubstituting 4-chlorobenzoic acid for 3-(4-methoxyphenyl)propionic acid.IR: C═O 1678 cm⁻¹. Elemental Analysis: calcd: Cl, 2.66%; N, 1.05%.Found: Cl, 2.39%; N, 1.02%.

EXAMPLE 22

N-Hydroxy-4-chlorobenzamide.

N-Hydroxy-4-chlorobenzamide is prepared by treatingN-(4-chlorobenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinwith TFA using the procedure of Example 7. LC MS (H-ISP) m/z 172,174(Cl) [M+H]⁺, Area=96%; ¹ H NMR (300 MHz, DMSO-d₆) δ 7.48 (d J=9.42, 2H),7.69 (d J=9.42, 2H), 8.9-9.2 (broad, 1H), 11.28 (s, 1H).

EXAMPLE 23

N-methyl-N-(4-chlorobenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR89##

N-(4-chlorobenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(0.1 g, 0.075 mmol, 0.75 mmol/g) is suspended in toluene (2 mL) andcooled to 5° C. The mixture is treated with methyl iodide (1.5 mmol,0.21 g, 93 μ) followed by DBU (0.22 mL, 0.228 g, 1.5 mmol ). Thereaction mixture is placed in a vortexer and allowed to warm to ambienttemperature. Within a few minutes a copious white precipitate forms andthe mixture is diluted further with toluene (2 mL). Agitation of thereaction mixture is continued for 18 hours. TheN-methyl-N-(4-chlorobenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinis filtered and washed with DMF, DMF/H₂ O, DMF, THF, Et₂ O and dried invacuo at 40° C.

EXAMPLE 24

1-(4-chlorophenyl)propan-1-one.

N-methyl-N-(4-chlorobenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinis suspended in diethyl ether (0.7 mL) and treated with ethyl magnesiumbromide (1.0 M in THF, 0.225 mL, 0.225 mmol). The reaction mixture isagitated for 18 hours on a wrist shaker and then quenched by theaddition of 5% HCl in ethanol. Agitation is maintained for a further 30minutes and the mixture is then filtered through a small plug of silicato remove the inorganic material. The filtrate is concentrated to afford1-(4-chlorophenyl)propan-1-one. MS (EI-LRP) m/z 168/170 Cl [M⁺ ],169/171 Cl [M+H]⁺ ; ¹ H NMR (300 Mhz, CDCl₃) δ 1.22 (t, 3H), 2.98 (q.2H), 7.42 (d, 2H), 7.9 (d, 2H).

EXAMPLE 25

N-[3-((4-methoxyphenyl)sulfonyl)propan-1-oylcarbonyl]-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR90##

N-[3-((4-methoxyphenyl)sulfonyl)propan-1-oylcarbonyl]-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinis prepared using the method of Example 16, except substituting added3-(4-methoxyphenylsulfonyl)propionic acid for3-(4-methoxyphenyl)propionic acid. IR C═O 1691.6 cm⁻¹ (broad). ElementalAnalysis: calcd: N, 1.02%; S, 2.34%. Found: N, 1.03%; S, 2.5%.

EXAMPLE 26

N-hydroxy-3-(4-methoxyphenylsulfonyl)propionamide.

N-hydroxy-3-(4-methoxyphenylsulfonyl)propionamide is prepared bytreatingN-[3-((4-methoxyphenyl)sulfonyl)propan-1-oylcarbonyl]-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinwith TFA using the procedure of Example 7. ¹ H NMR (300 Mhz, DMSO-d₆) δ2.25 (t, 2H), 3.42 (t, 2H) 3.85 (s, 31H), 7.13 (d, 2H), 7.79 (d, 2H); LCMS (Ion Spray) m/z 259 [M⁺ ], Area=44%

EXAMPLE 27

N-allyoxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin. ##STR91##

4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene)resin (2 g, 2 mmol) is suspended in 15 ml of dichloromethane and shakenon a wrist shaker for 10 minutes and 284 mg (383 μL, 2.2 mmol) ofdiisopropylethyl amine is added. The mixture is shaken for 30 minutes.Allyl chloroformate (265 mg, 233 μl, 2.2 mmol) is added and the mixtureis shaken overnight. TheN-allyoxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin is washed with 15 ml of dichloromethane, THF (3×)and dichloromethane (3×) and dried in vacuo.

EXAMPLE 28

N-4-bromobenzyl-N-allyoxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin. ##STR92##

TheN-allyoxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin prepared in Example 27 is suspended in 15 mL oftoluene. DBU (1,522 g, 1.5 ml, 10 mmol) and 4-bromobenzyl bromide (2.5g, 10 mmol) are added and the mixture is shaken for 70 hours. TheN-4-bromobenzyl-N-allyoxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin is washed with 15 mL of DMF (3×), THF (3×) anddichloromethane (3×) and dried in vacuo.

EXAMPLE 29

N-4-bromobenzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin. ##STR93##

N-4-bromobenzyl,N-allyoxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin, prepared as in Example 28, is swelled in 6 mL ofTHF, 6 mL of DMSO, 3 mL of 0.5 n HCl. Pd(Ph₃ P)₄ (347 mg, 15 weight %)is added and the mixture is shaken for 5 minutes. Morpholine (4.3 mL) isadded and the mixture is shaken overnight. The reagents are drained offand theN-4-bromobenzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin is washed with DMF (2×), THF (2×), dichloromethane(2×), 0.5% diisopropylethyl amine in dichloromethane (3×), 0.5% sodiumdiethyldithiocarbamate in DMF (3×), DMF (3×), THF (3×) anddichloromethane (3×) and dried in vacuo overnight.

EXAMPLE 30

N-(indol-2-ylcarbonyl)-N-4-bromobenzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin. ##STR94##

N-4-bromobenzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin (1.17 g, 1 mmole), prepared as in Example 29, issuspended in 15 ml of DMF. Indole-2-carboxylic acid (483 mg, 3 mmol) and575.1 mg (3 mmol) of 1(3-dimethylaminopropyl)-3diethylcarbodiimidehydrochloride are added and the mixture is shaken for 16 hours. TheN-(indol-2-ylcarbonyl)-N-4-bromobenzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin is drained and washed with 15 ml of DMF (3×),THF/20% H₂ O (3×), THF (3×), and dichloromethane (3×) and dried invacuo.

EXAMPLE 31

Indole-² -carboxaldehyde.

DryN-(indol-2-ylcarbonyl)-N-4-bromobenzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin is swelled in 12 mL of THF, shaken and cooled at0° C. for 30 minutes. LiAlH₄ (0.62 ml, 3 eq) is added and the mixture isshaken at 0° C. for 30 minutes. Saturated KHSO₄ solution (0.5 mL) and0.3 mL of potassium, sodium tartrate solution are added and the mixtureis shaken for 30 minutes while warming to room temperature. Excess H₂ Ois dried by adding dry Na₂ SO₄ and shaking for 15 minutes more. Themixture is filtered under low nitrogen pressure and washed 3 more timeswith 8 mL of dichloromethane followed by filtration. The filtrate isdried with Na₂ SO₄ and filtered twice through a short bed (1 inch) ofsilica gel 60 for column chromatography (particle size 0.040-0.063 mm)and the solvent is removed in vacuo to give indole-2-carboxaldehyde. ¹ HNMR (CDCl₃) δ 9.84 (1H,s), 9.22 (1H,brs), 7.75 (1H,d), 7.14-7.48 (4H,m);MS (EI): m/z=146 [M+H]⁺.

EXAMPLE 32

N-(3,4-dimethoxycinnamoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene)-resin. ##STR95##

4-Methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinresin (1 g, 1 mmole) is washed with DMF (15 mL), then suspended in 15 mLof DMF and 624.6 mg (3 mmole, 3× excess) of 3,4-dimethoxy cinnamic acidand 575.1 mg (3 mmol, 3× excess) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are addedand the mixture is shaken for 16 hours. The resin is drained and washedwith 15 mL of DMF (1×), THF/20% H₂ O (3×), THF (3×), dichloromethane(3×) and dried under vacuum overnight.

EXAMPLE 33

N-4-bromobenzyl-N-(3,4-dimethoxycinnamoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin.##STR96##

DryN-(3,4-dimethoxycinnamoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinis shaken in 15 mL of toluene for 10 minutes, then 0.9 mL (6 mmol, 6×excess) of DBU is added and the mixture is shaken for 2 hours. p-Bromobenzyl bromide (1.5 g, 6 mmol, 6× excess) is added and the mixture isshaken for 3 days. The resin is dried overnight in vacuo.

EXAMPLE 34

3-4-dimethoxycinnamaldehyde.

DryN-4-bromobenzyl-N-(3,4-dimethoxycinnamoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resinis swelled in 12 mL of dry THF, shaken and cooled to 0C for 30 minutes.LiAlH₄ in THF (0.5 mL, 2 equivalents) is added and the mixture is shakenat 0° C. for 30 minutes. Saturated aqueous KHSO₄ solution (0.5 mL) andpotassium, sodium tartrate solution (0.3 mL) are added and the mixtureis shaken for 30 minutes while warming to ambient temperature. Excess H₂O is dried by adding dry Na₂ SO₄ and shaking for 15 minutes. The mixtureis filtered under low nitrogen pressure, washed 3 times with 8 mL ofdichloromethane and filtered. The filtrate is further dried with Na₂ SO₄and filtered through a short (1 inch) bed of silica gel 60 for columnchromatography (particle size 0.040-0.063 mm) and the solvent is removedin vacuo to give 3,4-dimethoxycinnamaldehyde. ¹ H NMR (CDCl₃) δ 9.65(1H,d), 7.40 (1H,d), 7.12 (1H,d), 7.06 (1H,s), 6.87 (1H,d), 6.60(1H,dd), 3.90 (6H,s); MS (EI): m/z=193 [M+H⁺ ].

EXAMPLES 35-42

The compounds of Examples 35-42 are prepared from the desired carboxylicacid starting material using the procedures of Examples 32-34.

EXAMPLE 35

anthranilic aldehyde.

¹ H NMR (CDCl₃) δ 9.88 (1H,s), 7,52-7.58 (1H,d), 7.11-7.38 (7H,m), 6.81(1H,t); MS (EI): m/z=198 [M+H⁺ ].

EXAMPLE 36

2-bibenzylic aldehyde.

¹ H NMR (CDCl₃) δ 10.18 (1H,s), 7.83 (1H,d), 7.14-7.52 (8H,m), 3.30(2H,t), 2.87 (2H,t); MS (EI): m/z=211 [M+H⁺ ].

EXAMPLE 37

4-methoxy-2-quinoline aldehyde.

¹ H NMR (CDCl₃) δ 10.17 (1H,s), 8.27 (1H,d), 8.18 (1H,d), 7.78 (1H,t),7.62 (1H,t), 7.38 (1H,s), 4.12 (3H,s); MS (EI): m/z=188 [M+H⁺ ].

EXAMPLE 38

3-acetamido benzaldehyde.

¹ H NMR (CDCl₃) δ 9.98 (1H,s), 7.97 (1H,s), 7.86 (1H,d), 7.62 (1H,d),7.48 (1H,t), 2.21 (3H,s). MS (EI): m/z 164 [M+H⁺ ].

EXAMPLE 39

4-(4-N-propylphenyl) benzaldehyde.

¹ H NMR (CDCl₃) δ 10.02 (1H,s), 7,92 (2H,d), 7.72 (2H,d), 7.53 (2H,d),7.26 (2H,d), 2.65 (2H,t), 1.68 (2H, dt), 0.95 (3H,t); MS (EI): m/z=225[M+H⁺ ].

EXAMPLE 40

3-quinoline aldehyde.

¹ H NMR (CDCl₃) δ 10.26 (1H,s), 9.38 (1H,s), 8.64 (1H,s), 8.20 (1H,d),7.98 (1H,t), 7.89 (1H,t), 7.65 (1H,t); MS (EI): m/z=158 [M+H⁺ ].

EXAMPLE 41

3-(3,4-methylenedioxy) propionaldehyde.

¹ HNMR (CDCl₃) δ 9.80 (1H,s), 7.60-7.74 (3H,m), 5.92 (2H,s), 2.88(2H,t), 2.74 (2H,t); MS (EI): m/z=179 [M+H⁺ ].

EXAMPLE 42

2-phenyl-4-quinoline aldehyde.

¹ H NMR (CDCl₃) δ 10.58 (1H,s), 9.00 (1H,d) 8.19-8.30 (4H,m), 7.82(1H,t), 7.70 (1H,t), 7.47-7.59 (3H,m); MS (EI): m/z=234 [M+H⁺ ].

EXAMPLE 43

4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin. ##STR97##

Merrifield resin (2 mmol/g, 600 mg, 1.2 mmol) is swelled in anhydrousDMF (20 mL). 2,3,5,6-tetrafluoro-4-hydroxy benzoic acid hydrate (2.28 g,10 mmol) and cesium carbonate (3.26 g, 10 mmol) are added and thereaction mixture is heated at 85° C. for 12 hours with gentle agitation.The reaction mixture is filtered and the4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin is washed with DMF (5×), 20% aqueous DMF (5×), THF(5×) and dichloromethane and dried overnight in vacuo. IR (microscope,cm-1): 1640 (C═O); ¹⁹ F NMR (nanoprobe) -144.4 ppm, -160.2 ppm.

EXAMPLE 44

N-4-benzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin. ##STR98##

4-O-Methylhydroxylamine)phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin(2 g; 2 mmol), prepared as in Example 4, is swelled in DCM (15 ml), DIEA(0.383 ml; 2.2 mmol) is added and the mixture is shaken for 1 hour.Allyl chloroformate (0.234 ml; 2.2 mmol) is added and the mixture isshaken overnight. The resin is drained and washed three times each withDCM, THF and DCM and dried in vacuum. The dry resin is swelled inanhydrous toluene (18 ml), DBU (1.5 ml; 10 mmol) added and the mixtureis shaken for 1 hour. Benzyl bromide (1.19 ml; 10 mmol) is added and themixture is shaken for 3 days. The resin is drained and washed threetimes each with DCM, DMF, THF and DCM and dried overnight in vacuum. Tothe resin is added THF (6 ml), DMSO (6 ml), 0.5 N HCl (2.5 ml),tetrakis(triphenylphosphine)palladium(0) (347 mg; 15 mol %) andmorpholine (4.3 ml) and the mixture is shaken overnight. The resin isthen drained and washed in three times each with DMF, THF, DCM, 0.5% inDCM, 0.5% sodium diethyldithiocarbamate in DMF, DMF, THF and DCM andthen dried in vacuum. A resin sample is cleaved with excess 1:1 TFA/DCMfor 1 hour at ambient temperature, then washed three times with 1 ml ofthe cleavage mixture, evaporated and dried in vacuo. ¹ H NMR (CD₃ OD): δ7.44 (m, 5H), 4.36 (s, 2H); MS (EI): m/z=124 [M+H]⁺.

EXAMPLE 45

N-α-(tert-Butoxycarbonyl)-L-alaninal.

N-4-benzyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin (1.08 g; 1 mmole), prepared as in Example 45, iswashed with DMF (15 ml), suspended in 15 ml of DMF and Boc-Ala-OH (568mg; 3 mmol) and EDCl (575.1 mg; 3 mmol) are added and the mixture isshaken for 16 hours. The resin is drained and washed with 15 ml of DMF(2×), THF/20% H₂ O (3×), THF (3×), DCM (3×) and dried in vacuoovernight. The dry resin is swelled in 12 ml of anhydrous THF undernitrogen, shaken for 10 minutes and cooled to 0° C. for 30 min. LAH inTHF (0.75 ml; 3 mmol) is added and the mixture is shaken at 0° C. for 30minutes. Saturated KHSO₄ (0.5 ml) and K,Na tartrate (0.3 ml) solutionsare added and the reaction mixture is shaken for 20 minutes whilewarming to ambient temperature. Excess water is dried by addition of dryNa₂ SO₄ and shaking for 15 minutes. The mixture is filtered under lownitrogen pressure, washed three times with 8 ml of DCM and filtered. Thefiltrate is further dried with Na₂ SO₄ and filtered with DCM through ashort (1 inch) bed of silica gel 60 for column chromatography (particlesize 0.040-0.063 mm). Solvent removal and drying in vacuo afford 44 mgof the title compound. ¹ H NMR: δ 9.56 (s, 1H), 5.10 (brs, 1H), 4.22 (q,1H), 1.45 (m, 9H), 1.34 (d, 3H); MS (IS): m/z=173 [M⁺ ]. Purityestimated 90% by ¹ H NMR.

EXAMPLES 46-50

The following compound as prepared from the appropriate amino acidstarting material using the method of Example 46.

EXAMPLE 46

N-α-(tert-Butoxycarbonyl)-L-valinal.

¹ H NMR: δ 9.61 (s, 1H), 5.09 (brs, 1H), 4.27 (m, 1H), 1.80 (brm, 1H),1.48 (m, 9H), 1.03 (d, 3H), 0.95 (d, 3H); MS (IS): m/z=201 [M⁺ ]. Purityestimated 90% by ¹ H NMR.

EXAMPLE 47

N-α-(tert-Butoxycarbonyl)-L-phenylalaninal.

¹ H NMR: δ 9.62 (s, 1H), 7.12-7.34 (m, 5H), 5.04 (brs, 1H), 4.42 (t,1H), 3.09 (d, 2H), 1.39 (s, 9H); MS (IS): m/z=250 [M+H]⁺ LC Area(UV₂₂₀)=91%.

EXAMPLE 48

N-α-(tert-Butoxycarbonyl)-β-(t-butyl)-L-aspartal.

¹ H NMR: δ 9.63 (s, 1H), 5.60 (brs, 1H), 2.82 (m, 2H), 2.02 (m, 1H),1.42 (m, 18H); MS (IS): m/z=274 [M+H]⁺ LC Area (UV₂₂₀)=80%.

EXAMPLE 49

N-α-(tert-Butoxycarbonyl)-N-ε-(tert-butoxycarbonyl)-L-lysinal-OH.

¹ H NMR: δ 9.53 (s, 1H), 5.21 (brs, 1H), 3.12 (m, 2H), 1.88 (m, 2H),1.18-1.66 (m, 22H); MS (IS): m/z=331 [M+H]⁺ LC Area (UV₂₂₀)=67%.

EXAMPLE 50

Indole-2-carboxaldehyde.

¹ H NMR: δ 9.82 (s, 1H), 7.14-7.75 (m, 6H); MS (EI): m/z=145 [M⁺ ] LCArea (UV254)=90%.

EXAMPLES 51-101

Parallel Synthesis of Arrays of Anthranilic Acid Compounds ##STR99##

The Parallel syntheses are accomplished using a Tecan Combitec organicsynthesis robot. Forty eight reaction vessels are placed in the robot'sreaction block and a slurry of ethyl phosphonate resin compound in THFis transferred by pipette into each of the reaction vessels. For thissynthesis it is found to be more convenient to load the phosphonates tothe resin on a large scale, then split the resin into the reactionblock. The robot dispenses anhydrous THF to the reaction vessels,followed by the solution of base (1.0 molar in THF) as they sit on thedeck of the robot in an ice bath. The sixteen aldehydes (see Table 1)are prepared as 0.5 molar solutions in 60% cyclohexane in THF. Thereaction block is then manually moved to an orbital shaker and agitatedfor one hour at ambient temperature. The reaction block is then placedback on the instrument. The vessels are then drained, and solutions ofthe aldehydes are dispensed to their respective reaction vessel. Thereaction block is then moved to an orbital shaker and agitated for 2-3days at ambient temperature. Work-up of the reaction on the robotconsists of draining the vessels and washing the resin with THF, 20%aqueous DMF, DMF, THF, and then dichloromethane. A total of 21 washesare needed to remove all the impurities in the resin matrix. The resinis then sampled for single bead FT IR analysis. The diagnostic carbonylshift is a qualitative means of determining whether the reaction hasgone to completion.

The anthranilic acid products are then cleaved from the resin using 30%trifluoroacetic acid (TFA) in dichloromethane. The TFA solutions aretransferred to pre-tared test tubes contained in a Benchmate 116compatible 5×10 position rack, which had been defined on the deck of therobot. This format effectively couples sample concentration andweighing. Sample concentration is achieved using the Zymark Turbovapconcentrator, in which the Benchmate II compatible rack fits, forefficient nitrogen blow-down of the samples. The Benchmate II compatiblerack containing the desired samples is then placed in a Zymark Turbovapconcentrator to remove the solvent (the Turbovap had been modifiedslightly by coating the manifolds with Teflon to prevent corrosion ofthe gas nozzles). The forty eight samples each containing approximately3 mL of 30% TFA in dichloromethane are concentrated in about thirtyminutes. The samples are usually chased with a one milliliter portion ofmethanol, then re-evaporated, to ensure complete removal of the TFAsolution. The reaction set is then analyzed by ¹ H NMR and LC-MS (SeeTable 1).

                  TABLE 1                                                         ______________________________________                                                           IR Resin       Anthranilic                                     C═O  Acid Purity                                                        Example R.sub.m Stretch R.sub.n (A % @ UV.sub.220)                          ______________________________________                                          51 Et 1733 -- --                                                              52 Ph(CH.sub.2).sub.3 -- 1733 -- --                                           53 H 1737 -- --                                                               54 Et 1707 A 81                                                               55 Et 1704 B 92                                                               56 Et 1711 C 95                                                               57 Et 1699 D 85                                                               58 Et 1703 E 95                                                               59 Et 1708 F 95                                                               60 Et 1706 G 85                                                               61 Et 1709 H 90                                                               62 Et 1708 I 96                                                               63 Et 1705 J 97                                                               64 Et 1704 K 77                                                               65 Et 1706 L 95                                                               66 Et 1707 M 50                                                               67 Et 1705 N 93                                                               68 Et 1703 O 81                                                               69 Et 1703 P 80                                                               70 Ph(CH.sub.2).sub.3 -- 1707 A 93                                            71 Ph(CH.sub.2).sub.3 -- 1705 B 88                                            72 Ph(CH.sub.2).sub.3 -- 1711 C 89                                            73 Ph(CH.sub.2).sub.3 -- 1699 D 87                                            74 Ph(CH.sub.2).sub.3 -- 1703 E 88                                            75 Ph(CH.sub.2).sub.3 -- 1708 F 82                                            76 Ph(CH.sub.2).sub.3 -- 1707 G 90                                            77 Ph(CH.sub.2).sub.3 -- 1708 H 86                                            78 Ph(CH.sub.2).sub.3 -- 1708 I 97                                            79 Ph(CH.sub.2).sub.3 -- 1704 J 91                                            80 Ph(CH.sub.2).sub.3 -- 1704 K 76                                            81 Ph(CH.sub.2).sub.3 -- 1705 L 93                                            82 Ph(CH.sub.2).sub.3 -- 1706 M 73                                            83 Ph(CH.sub.2).sub.3 -- 1705 N 80                                            84 Ph(CH.sub.2).sub.3 -- 1702 O 95                                            85 Ph(CH.sub.2).sub.3 -- 1702 P 83                                            86 H 1712 A 76                                                                87 H 1711 B 87                                                                88 H 1717 C 93                                                                89 H 1706 D 48                                                                90 H 1708 E 90                                                                91 H 1711 F 75                                                                92 H 1708 G 50                                                                93 H 1712 H 85                                                                94 H 1714 I 70                                                                95 H 1711 J 81                                                                96 H 1708 K 90                                                                97 H 1711 L 85                                                                98 H 1711 M 74                                                                99 H 1711 N 76                                                                100  H 1711 O 75                                                              101  H 1711 P 89                                                            ______________________________________                                          A =                                                                                  #STR100##                                                               - B =                                                                               #STR101##                                                               - C =                                                                               #STR102##                                                               - D =                                                                               #STR103##                                                               - E =                                                                               #STR104##                                                               - F =                                                                               #STR105##                                                               - G =                                                                               #STR106##                                                               - H =                                                                               #STR107##                                                               - I =                                                                               #STR108##                                                               - J =                                                                               #STR109##                                                               - K =                                                                               #STR110##                                                               - L =                                                                               #STR111##                                                               - M =                                                                               #STR112##                                                               - N =                                                                               #STR113##                                                               - O =                                                                               #STR114##                                                               - P =                                                                              ##STR115##                                                            ______________________________________                                    

EXAMPLE 102

3-(3,4-dimethoxybenzenesulfonyl)-5-methylhexanoic acid hydroxyamide.

Step A: Wang resin (20 g, 15 mmol) is swelled in 300 mL of anhydrous DMFfor 15 minutes. Then a solution of diethyl phosphonoacetic acid (8.83 g,45 mmol) in 50 mL of DMF is added followed by pyridine (7.12 g, 90 mmol)and 2,6-dichlorobenzoyl chloride (9.4 g, 45 mmol). The mixture isagitated for 20 hours at room temperature. The resin is filtered andwashed successively with DMF (3×), H₂ O (3×), DMF (3×), THF (10×) andEt₂ O (10×) followed by drying in vacuo at 40° C. for 20 hours. IR(micro) u c=o 1738 cm⁻¹

Step B: The loaded resin from Step A (1 g, 0.75 mmol) is swelled inanhydrous THF (10 mL) for 15 minute followed by the addition of a 0.5 Msolution of potassium bis(trimethylsilyl)amide in toluene (4 mL) at 0°C. The mixture is allowed to warm up to room temperature and is shakenfor 30 minutes. The solvent is then drained to the top of the resinfollowed by the addition of anhydrous cyclohexane (10 mL) andisovaleraldehyde (0.17 g, 2 mmol). The mixture is shaken forapproximately 72 hours and worked up as described in Step A. IR (micro)u c=o 1718 cm⁻¹

Step C: To a solution of 3,4-dimethoxybenzenethiol (11.9 g, 70 mmol) inanhydrous THF (54.4 mL) at 0° C. is added a 2.5 M solution ofn-butyllithium (5.6 mL, 14 mmol) and the solution is stirred at roomtemperature for 15 minutes.

The resin from Step B (0.25 g, 0.19 mmol) is swelled in anhydrous THF(2.5 mL) for 15 minutes and 4 mL of the above prepared 1 Nthiol/thiolate stock solution is added. The mixture is shaken forapproximately 100 hours and worked up as described in Step A. IR (micro)u c=o 1732 cm⁻¹

Step D: The resin from step 3 (0.25 g, 0.19 mmol) is swelled in1,4-dioxane (5 mL) for 15 minutes and a solution ofm-chloroperoxybenzoic acid (0.44 g, 2.5 mmol) in 2 mL of 1,4-dioxane isadded. The mixture is shaken for 16 hours and worked up as described inStep A.

Step E: The resin from Step D (0.25 g, 0.19 mmol) is treated with 1:1dichloro-methane/trifluoroacetic acid (3 mL) for 1-2 hours. The resin isfiltered and washed with dichloromethane (2×1 mL). The combinedfiltrates are concentrated in vacuo to provide3-(3,4-dimethoxybenzenesulfonyl)-5-methylhexanoic acid (9.8 mg). ¹ H NMR(300 MHz, CDCl₃) δ 0.85 (d, 3H), 0.92 (d, 3H), 1.4 (m, 1H), 1.6-1.8 (m,2H), 2.55 (dd, 1H), 2.9 (dd, 1H), 3.65 (m, 1H), 3.92 (s, 3H), 3.95 (s,3H), 7.0 (d, 1H), 7.32 (s, 1H), 7.5 (d, 1H). MS (APCI; Loop) m/z 348(M+NH₄)⁺, 331 (M+H)⁺.

Step F: The hydroxylamine bound Wang resin (50 mg, 0.037 mmol) isswelled in anhydrous DMF (1 mL) for 15 minutes followed by the additionof 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg,0.16 mmol) and a solution of the carboxylic acid from Step E in 1 mL ofanhydrous DMF. The mixture is shaken for 20 hours and worked up asdescribed in Step A.

Step G: The resin from Step F is treated with 1:1dichloromethane/trifluoroacetic acid (2 mL) for 1.5 hours. The resin isfiltered and washed with dichloro-methane (2×1 mL). The combinedfiltrates are concentrated in vacuo to provide3-(3,4-dimethoxybenzenesulfonyl)-5-methylhexanoic acid hydroxyamide (9.8mg). MS (H-isp; LCMS) m/z 363 (M+NH₄)⁺, 346 (M+H)⁺.

EXAMPLES 103-128

The following hydroxamic compounds are synthesized using appropriatestarting materials and following the steps of this example:

EXAMPLE 103

5-(4-Butoxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)-pentanoic acidhydroxyamide.

MS (APCI; LCMS) m/z 466 (M+H)⁺

EXAMPLE 104

3-(3,4-Dimethoxybenzenesulfonyl)hexanoic acid hydroxyamide.

MS (H-isp; LCMS) m/z 332 (M+H)⁺

EXAMPLE 105

3-(3,4-Dimethoxybenzenesulfonyl)-4-methylpentanoic acid hydroxyamide.

MS (H-isp; LCMS) m/z 332 (M+H)⁺

EXAMPLE 106

3-(3,4-Dimethoxybenzenesulfonyl)-5-methylhexanoic acid hydroxyamide.

MS (H-isp; LCMS) m/z 346 (M+H)⁺

EXAMPLE 107

3-(3-Benzyloxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)-N-hydroxypropionamide.

MS (H-isp; LCMS) m/z 472 (M+H)⁺

EXAMPLE 108

3-(2-Benzyloxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)-N-hydroxypropionamide.

MS (APCI; LCMS) m/z 472 (M+H)⁺

EXAMPLE 109

3-(3-Benzyloxy-4-methoxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)-N-hydroxypropionamide.

MS (APCI; LCMS) m/z 502 (M+H)⁺

EXAMPLE 110

3-(3,4-Dimethoxybenzenesulfonyl)-N-hydroxy-3-(3-phenoxyphenyl)propionamide.

MS (APCI; LCMS) m/z 458 (M+H)⁺

EXAMPLE 111

3-(3-(4-Chlorophenoxy)phenyl)-3-(3,4-dimethoxybenzenesulfonyl)-N-hydroxypropionamide.

MS (H-isp; LCMS) m/z 492 (M+H)⁺

EXAMPLE 112

3-(3,4-Dimethoxybenzenesulfonyl)-N-hydroxy-3-(3-(4-methoxy-phenoxy)phenyl)propionamide.

MS (H-isp; LCMS) m/z 488 (M+H)⁺

EXAMPLE 113

2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-4-methylpentanoicacid hydroxyamide via2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)-methyl]-4-methylpentanoicacid.

¹ H NMR (300 MHz, CDCl₃) δ 0.9-1.1 (2×d, 6H), 1.6 (m, 1H), 1.9 (m,1H),2.35 (m, 1H), 3.55 (s, 3H), 3.7 (m, 1H), 3.9 (s, 3H), 4.3 (d, 1H),6.6-7.5 (series m, 12H). MS (APCI; LCMS) m/z 500 (M+NH₄)⁺, 483 (M+H)⁺yields2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-4-methylpentanoicacid hydroxyamide (4.9 mg). MS (APCI; LCMS) m/z 515 (M+NH₄)⁺, 498(M+H)⁺.

EXAMPLE 114

2-[(3,4-Dimethoxybenzenesulfonyl)-(4-phenoxyphenyl)methyl]-N-hydroxy-4-(2-methoxyethoxy)butyramide.

MS (APCI; LCMS) m/z 560 (M+H)⁺.

EXAMPLE 115

2-[(3,4-Dimethoxybenzenesulfonyl)-(4-phenoxyphenyl)methyl]-N-hydroxy-butyramide.

MS (APCI; LCMS) m/z 486(M+H)⁺.

EXAMPLE 116

4-Benzenesulfonyl-2-[biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxybutyramide.

MS (isp; Loop) m/z 610 (M+H)⁺.

EXAMPLE 117

2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxy-4-phenyl-butyramide.

MS (APCI; LCMS) m/z 546 (M+H)⁺.

EXAMPLE 118

2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxy-4-(2-methoxy-ethoxy)-butyramide.

MS (isp; Loop) m/z 544 (M+H)⁺.

EXAMPLE 119

2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxybutyramide.

MS (APCI; LCMS) m/z 470 (M+H)⁺.

EXAMPLE 120

2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-4-methylpentanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 498 (M+H)⁺.

EXAMPLE 121

2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-N-hydroxy-3-methyl-butyramide.

MS (APCI; LCMS) m/z 484 (M+H)⁺.

EXAMPLE 122

2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-7-phenylheptanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 588 (M+H)⁺.

EXAMPLE 123

2-[Biphenyl-4-yl-(3,4-dimethoxybenzenesulfonyl)methyl]-5-phenylpentanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 560 (M+H)⁺.

EXAMPLE 124

2-[(3,4-Dimethoxybenzenesulfonyl)-(4-phenoxyphenyl)methyl]-N-hydroxy-3-methyl-butyramide.

MS (APCI; LCMS) m/z 500 (M+H)⁺.

EXAMPLE 125

2-[(3,4-Dimethoxybenzenesulfonyl)-(4-phenoxyphenyl)methyl]-7-phenylheptanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 604 (M+H)⁺.

EXAMPLE 126

3-(3,4-Dimethoxybenzenesulfonyl)-2-ethylhexanoic acid hydroxyamide.

Modified procedure for Step C: Reaction temperature=60° C., Reactiontime=2×20 hours.

MS (APCI; LCMS) m/z 360 (M+H)⁺.

EXAMPLE 127

3-(3,4-Dimethoxybenzenesulfonyl)-2-(3-phenyl-propyl)hexanoic acidhydroxyamide.

Modified procedure for Step C. Reaction temperature=60° C., Reactiontime=2×20 hours.

MS (APCI; LCMS) m/z 450 (M+H)⁺.

EXAMPLE 128

2-[(3-Benzyloxyphenyl)-(3,4-dimethoxybenzenesulfonyl)methyl]-5-phenylpentanoicacid hydroxyamide.

Modified procedure for Step C. Reaction temperature=60° C., Reactiontime=2×20 hours.

MS (APCI; Loop) m/z 590 (M+H)⁺.

EXAMPLES 129-142

Step A: The hydroxylamine bound Rink resin (0.1 g, 0.031 mmol) isswelled in anhydrous DMF (1 mL) for 15 minutes followed by the additionof 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg,0.16 mmol) and a solution of the appropriate carboxylic acid prepared asin Example 54, Steps A-E in 1 mL of anhydrous DMF. The mixture is shakenfor 20 hours and worked up as described in Example 54, Step A.

Step B: The resin from Step A (0.1 g, 0.031 mmol) is treated with 9:1dichloromethane/trifluoroacetic acid (2 mL) for 1 hour. The resin isfiltered and washed with dichloromethane (2×1 mL). The combinedfiltrates are concentrated in vacuo to provide the following hydroxamicacids:

EXAMPLE 129

N-[2-(3,4-Dimethoxybenzenesulfonyl)-3-hydroxycarbamoyl-propyl]-Nmethyl-benzamide.

MS (APCI; Loop) m/z 437 (M+H)⁺

EXAMPLE 130

N-[2-(3,4-Dimethoxybenzenesulfonyl)-3-hydroxycarbamoyl-butyl]-Nmethyl-benzamide.

MS (APCI; Loop) m/z 451 (M+H)⁺

EXAMPLE 131

Methyl-phenyl-carbamic acid3-(3,4-dimethoxybenzenesulfonyl)-4-hydroxycarbamoyl-butyl ester.

MS (APCI; Loop) m/z 452 (M+H)⁺ -15

EXAMPLE 132

[3-(3,4-Dimethoxybenzenesulfonyl)-4-hydroxycarbamoyl-butyl]methyl-carbamicacid benzyl ester.

MS (APCI; Loop) m/z 481 (M+H)⁺

EXAMPLE 133

3-(3,4-Dimethoxybenzenesulfonyl)hexanedioicacid-1-hydroxyamide-6-(methyl-phenyl-amide).

MS (APCI; Loop) m/z 451 (M+H)⁺

EXAMPLE 134

3-(3,4-Dimethoxybenzenesulfonyl)heptanedioicacid-1-hydroxyamide-7-(methyl-phenyl-amide).

MS (APCI; Loop) m/z 465 (M+H)⁺

EXAMPLE 135

3-(3,4-Dimethoxybenzenesulfonyl)-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)hexanoicacid hydroxyamide. MS (APCI; Loop) m/z 477 (M+H)⁺

EXAMPLE 136

7-(3,4-Dihydro-2H-quinolin-1-yl)-3-(3,4-dimethoxybenzenesulfonyl)-7-oxo-heptanoicacid hydroxyamide.

MS (APCI; Loop) m/z 491 (M+H)⁺

EXAMPLE 137

7-(3,4-Dihydro-2H-quinolin-1-yl)-3-(3,4-dimethoxybenzenesulfonyl)-6-oxo-hexanoicacid hydroxyamide.

MS (APCI; Loop) m/z 477 (M+H)⁺

EXAMPLE 138

7-Benzo(1,3)dioxol-5-yl-3-(3,4-dimethoxybenzenesulfonyl)heptanoic acidhydroxyamide.

MS (APCI; Loop) m/z 466 (M+H)⁺

EXAMPLE 139

3-(3,4-Dimethoxybenzenesulfonyl)-3-(thien-3-yl)-N-hydroxypropionamide.

MS (APCI; Loop) m/z 372 (M+H)⁺

EXAMPLE 140

3-(3,4-Dimethoxybenzenesulfonyl)-5-phenylpentanoic acid hydroxyamide.

MS (APCI; Loop) m/z 394 (M+H)⁺

EXAMPLE 141

3-(3,4-Dimethoxybenzenesulfonyl)-5-(3-phenoxyphenyl)pentanoic acidhydroxyamide.

MS (APCI; Loop) m/z 486 (M+H)⁺

EXAMPLE 142

5-(4-Benzyloxyphenyl)-3-(3,4-dimethoxybenzenesulfonyl)pentanoic acidhydroxyamide.

MS (APCI; Loop) m/z 500 (M+H)⁺

EXAMPLE 143

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyoxy-phenyl]methyl}-4-methylpentanoicacid hydroxyamide.

Step A: Wang resin (2 g, 1.5 mmol) is swelled in 20 mL of anhydrous DMFfor 15 minutes. Then a solution of the phosphonoacetic acid in DMF (1.13g, 4.5 mmol) is added followed by pyridine (0.71 g, 9 mmol) and2,6-dichloro-benzoyl chloride (0.94 g, 4.5 mmol). The mixture isagitated for 20 hours at room temperature. The resin is filtered andwashed successively with DMF (3×), H₂ O (3×), DMF (3×), THF (10×) andEt₂ O (10×) followed by drying in vacuo at 40° C. for 20 hours. IR(micro) u c=o 1730 cm⁻¹

Step B: The loaded resin from Step A (0.5 g, 0.375 mmol) is swelled inanhydrous THF (5 mL) for 15 minute followed by the addition of a 0.5 Msolution of potassium bis(trimethylsilyl)amide in toluene (2 mL) at 0°C. The mixture is allowed to warn up to room temperature and is shakenfor 30 minutes. The solvent is drained to the top of the resin followedby the addition of anhydrous cyclohexane(10 mL) and the aldehyde (0.25g, 1 mmol). The mixture is shaken for approximately 72 hours and workedup as described in Step A. IR (micro) u c=o 1704 cm⁻¹

Step C: To a solution of 3,4dimethoxybenzenethiol(l 1.9 g, 70 mmol) inanhydrous THF (54.4 mL) at 0° C. is added a 2.5 M solution ofn-butyllithium (5.6 mL, 14 mmol) and the solution is stirred at roomtemperature for 15 minutes.

The resin from step 2 (0.2 g, 0.15 mmol) is swelled in anhydrous THF(2.5 mL) for 15 minutes and 4 mL of the above prepared 1 Nthiol/thiolate stock solution is added. The mixture is shaken forapproximately 100 hours and worked up as described in step 1. The thioladdition did not go to completion as evidenced by IR spectra (u c=o 1703cm⁻¹). The reaction is driven to completion by repeating the aboveprocedure twice. IR (micro) u c=o 1731 cm⁻¹

Step D: The resin from Step C (0.2 g, 0.15 mmol) is swelled in dioxane(5 mL) for 15 minutes and a solution of m-chloroperoxybenzoic acid (0.44g, 2.5 mmol) in 2 mL of dioxane is added. The mixture is shaken for 16hours and worked up as described in step 1.

Step E: The resin from Step D (0.2 g, 0.15 mmol) is treated with 1:1dichloro-methane/trifluoroacetic acid (3 mL) for 1-2 hours. The resin isfiltered and washed with dichloromethane (2×1 mL). The combinedfiltrates are concentrated in vacuo to provide2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxyphenyl]methyl}-4-methylpentanoicacid (40 mg). ¹ H NMR (300 MHz, CDCl₃) δ 0.7-1.1 (2×d, 6H), 1.55 (m,1H), 1.85 (m, 1H), 2.35 (m, 1H), 3.65 (s, 3H), 3.85 (s, 3H), 4.18 (d,1H), 4.9 (s, 2H), 6.6-7.4 (series of m, 11H). MS (H-isp; Loop) m/z 548(M+NH₄)⁺, 531 (M+H)⁺.

Step F: The hydroxylamine bound Rink resin (0.1 g, 0.031 mmol) isswelled in anhydrous DMF (1 mL) for 15 minutes followed by the additionof 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg,0.1 mmol) and a solution of the carboxylic acid from step 5 in 1 mL ofanhydrous DMF. The mixture is shaken for 20 hours and worked up asdescribed in step A.

Step G: The resin from Step F (0.1 g, 0.031 mmol) is treated with 9:1dichloro-methane/trifluoroacetic acid (2 mL) for 1 hour. The resin isfiltered and washed with dichloromethane (2>1 mL). The combinedfiltrates are concentrated in vacuo to provide2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy-phenyl]methyl}-4-methylpentanoicacid hydroxyamide (2.3 mg). MS (H-isp; LCMS) m/z 546 (M+H)⁺.

EXAMPLES 144-164

The following hydroxamic compounds are synthesized using appropriatestarting materials and following the steps of this example:

EXAMPLE 144

3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-(4-phenylbutyl)heptanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 554 (M+H)⁺.

EXAMPLE 145

2-[1-(3-(3,4-dimethoxybenzenesulfonyl)-5-phenylpentyl]-N 1-hydroxy-N4-methyl-N 4-phenylsuccinamide.

MS (APCI; LCMS) m/z 568 (M)⁺.

EXAMPLE 146

3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-(3-phenylpropyl)heptanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 540 (M+H)⁺.

EXAMPLE 147

3-(3,4-dimethoxybenzenesulfonyl)-2-isopropyl-7-phenylheptanoic acidhydroxyamide.

MS (APCI; LCMS) m/z 464 (M+H)⁺.

EXAMPLE 148

3-(3,4-dimethoxybenzenesulfonyl)-2-isobutyl-7-phenylheptanoic acidhydroxyamide.

MS (APCI; LCMS) m/z 478 (M+H)⁺.

EXAMPLE 149

3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-propylheptanoic acidhydroxyamide.

MS (APCI; LCMS) m/z 464 (M+H)⁺.

EXAMPLE 150

3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-(4-phenyl-butyl)heptanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 450 (M+H)⁺.

EXAMPLE 151

3-(3,4-dimethoxybenzenesulfonyl)-2-[2-(2-methoxyethoxy)ethyl]-7-phenylheptanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 524 (M+H)⁺.

EXAMPLE 152

3-(3,4-dimethoxybenzenesulfonyl)-2-benzenesulfonylethyl-7-phenylheptanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 590 (M+H)⁺.

EXAMPLE 153

3-(3,4-dimethoxybenzenesulfonyl)-7-phenyl-2-(5-phenylpentyl)heptanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 568 (M+H)⁺.

EXAMPLE 154

4-Benzenesulfonyl-2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N-hydroxy-butyramide.

MS (APCI; LCMS) m/z 658 (M+H)⁺.

EXAMPLE 155

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N-hydroxy-4-phenyl-butyramide.

MS (APCI; LCMS) m/z 594 (M+H)⁺.

EXAMPLE 156

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N-hydroxy-4-(2-methoxyethoxy)butyramide.

MS (APCI; LCMS) m/z 592 (M+H)⁺.

EXAMPLE 157

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl }-N-hydroxy-butyramide.

MS (APCI; LCMS) m/z 518 (M+H)⁺.

EXAMPLE 158

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-pentanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 532 (M+H)⁺.

EXAMPLE 159

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-4-methylpentanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 546 (M+H)⁺.

EXAMPLE 160

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N-hydroxy-3-methylbutyramide.

MS (APCI; LCMS) m/z 532 (M+H)⁺.

EXAMPLE 161

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-7-phenylheptanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 636 (M+H)⁺.

EXAMPLE 162

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-5-phenylpentanoicacid hydroxyamide.

MS (APCI; LCMS) m/z 608 (M+H)⁺.

EXAMPLE 163

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-N1-hydroxy-N 4-methyl-N 4-phenyl-succinimide.

MS (APCI; LCMS) m/z 637 (M+H)⁺.

EXAMPLE 164

2-{(3,4-dimethoxybenzenesulfonyl)-[4-(4-fluorobenzyloxy)phenyl]methyl}-6-phenylhexanoic acid hydroxyamide.

MS (APCI; LCMS) m/z 622 (M+H)⁺.

EXAMPLE 165

3-(4-methoxybenzenesulfonyl)-3-(4-ethoxyphenyl)propionic acidhydroxyamide.

Step A: Wang resin (20 g, 15 mmol) is swelled in 300 mL of anhydrous DMFfor 15 minutes. Then a solution of diethyl phosphonoacetic acid (8.83 g,45 mmol) in 50 mL of DMF is added followed by pyridine (7.12 g, 90 mmol)and 2,6-dichlorobenzoyl chloride (9.4 g, 45 mmol). The mixture isagitated for 20 hours at room temperature. The resin is filtered andwashed successively with DMF (3×), H₂ O (3×), DMF (3×), THF (10×) andEt₂ O (10×) followed by drying in vacuo at 40° C. for 20 hours. IR(micro) u c═O 1738 cm⁻¹

Step B: The loaded resin from Step A (1 g; 0.63 mmol) is swelled inanhydrous THF (10 mL) for 15 minute followed by the addition of a 1 Msolution of lithium bis(trimethylsilyl)amide in THF (1.6 mL; 1.57equiv.) at 0° C. The mixture is allowed to warm up to room temperatureand is shaken for 30 minutes. The solvent is then drained to the top ofthe resin followed by the addition of anhydrous cyclohexane (10 mL) and4-ethoxy-benzaldehyde (0.5 g; 3.3 mmol). The mixture is shaken forapproximately 72 hours. The resin is then filtered and washedsuccessively with DMF (3×), H₂ O (3×), DMF (3×), THF (10×) and Et₂ O(10×) followed by drying in vacuo at 40° C. for 20 hours. IR (micro) uc=o 1709 cm⁻¹

Step C: To a solution of 4-methoxybenzene thiol (0.6 mL; 5 mmol) inanhydrous THF (1 mL) at 0° C. is added n-butyllithium (2.5 M in hexanes;0.02 mL; 0.05 mmol) and the solution is stirred at room temperature for15 minutes. The resin from step 2 (1 g; 0.63 mmol) contained in apolypropylene peptide synthesis cartridge is swelled in anhydrous THF(10 mL) for 15 minutes. The above prepared 1 N thiol/thiolate stocksolution is added. The mixture is shaken for approximately 100 hours.The resin is then filtered and washed successively with DMF (3×), H₂ O(3×), DMF (3×), THF (10×) and Et₂ O (10×) followed by drying in vacuo at40° C. for 20 hours. IR (micro) u c=o 1734 cm⁻¹

Step D: The resin from Step C (1 g, 0.63 mmol) is swelled in 1,4-dioxane(5 mL) for 15 minutes and a solution of m-chloroperoxybenzoic acid(0.863 g; 5 mmol) in 2 mL of 1,4-dioxane is added. The mixture is shakenfor 16 hours, the resin is then filtered and washed successively withDMF (3×), H₂ O (3×), DMF (3×), THF (10×) and Et₂ O (10×) followed bydrying in vacuo at 40° C. for 20 hours.

Step E: The resin from Step D (1 g, 0.63 mmol) is treated with 1:1dichloromethane/trifluoroacetic acid (8 mL) for 1-2 hours. The resin isfiltered and washed with dichloromethane (2×1 mL). The combinedfiltrates are concentrated in vacuo to provide3-(4-methoxybenzenesulfonyl)-3-(ethoxy-phenyl)propionic acid (84 mg;34%). ¹ H NMR (300 MHz, CDCl₃ -d3) δ 1.42 (t, J=9.0 Hz, 3H); 3.08 (dd,J=10.8 Hz, 1H); 3.44 (dd, J=7.2 Hz, 1H); 3.86 (s, 3H ); 4.02 (q, J=9.0Hz, 2H); 4.54 (dd, J=7.1 Hz, 1H); 6.72 (d, J=12.6 Hz, 2H); 6.82 (d,J=12.3 Hz, 2H); 6.98 (d, J=12.4 Hz, 2H); 7.42 (d, J=12.3 Hz, 2H); 7.52(bs, 1H). MS (H-isp; LCMS); m/z=387 [M+Na]⁺, 382 [M+NH₄ ]⁺, 365 [M+H]⁺.

Step F: The hydroxylamine bound Rink resin (200 mg, 0.04 mmol) isswelled in anhydrous DMF (1 mL) for 15 minutes followed by the additionof 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg,0.2 mmol) and a solution of the carboxylic acid from step 5 (84 mg; 0.2mmol) in 1 mL of anhydrous DMF. The mixture is shaken for 20 hours. Theresin is then filtered and washed successively with DMF (3×), H₂ O (3×),DMF (3×), THF (10×) and Et₂ O (10×) followed by drying in vacuo at 40°C. for 20 hours.

Step G: The resin from Step F (200 mg; 0.04 mmol) is treated with 1:1dichloromethane/trifluoroacetic acid (3 mL) for 30 minutes. The resin isfiltered and washed with dichloromethane (2×1 mL). The combinedfiltrates are concentrated in vacuo to provide3-(4-methoxybenzenesulfonyl)-3-(4-ethoxyphenyl)propionic acidhydroxyamide (9.6 mg). MS (H-isp; LCMS); m/z=402 [M+Na]⁺, 380 [M+H]⁺.

EXAMPLES 166-170

The following hydroxamic compounds are synthesized using appropriatestarting materials and following the steps of Example 165.

EXAMPLE 166

3-(4-methoxybenzenesulfonyl)-3-(4-biphenyl)propionic acid hydroxyamide)

MS (H-isp; LCMS); m/z=412 [M+H]⁺. A %=89% @ 220 nm

EXAMPLE 167

3-(4-methoxybenzenesulfonyl)-3-(4-phenoxyphenyl)propionic acid hydroxyamide

MS (H-isp; LCMS); m/z=428 [M+H]⁺. A %=75% @ 220 nm

EXAMPLE 168

3-(4-methoxybenzenesulfonyl)-3-(4-benzyloxyphenyl)-propionic acidhydroxy amide

MS (H-isp; LCMS); m/z=442 [M+H]⁺. A %=60% @ 220 nm

EXAMPLE 169

3-(4-methoxybenzenesulfonyl)-3-(4-fluorobenzyloxyphenyl)-propionic acidhydroxy amide

MS (H-isp; LCMS); m/z=460 [M+H]⁺. A %=68% @ 220 nm

EXAMPLE 170

3-(4-methoxybenzenesulfonyl)-3-(4-(3-trifluoromethylphenoxy)-phenyl-propionicacid hydroxy amide

MS (H-isp; LCMS); m/z=496 [M+H]⁺. A %=74% @ 220 nm

EDS

The energy dispersive x-ray measurements are made with an ElectroscanScanning Electron Microscope with an attached PGT digital detector. Thebeads are mounted on aluminum stubs and tested without a conductivecoating. The net x-ray counts are reported after correction for thebackground. No corrections are made for atomic number, fluorescence orabsorption.

What is claimed is:
 1. A process for the preparation of a ketonecompound of formula ##STR116## wherein R_(c) and R_(a) are independentlyaliphatic or aromatic comprising(a) reacting an N-alkylated polymerichydroxamic acid resin compound of formula ##STR117## wherein is a solidsupport, L is absent or a linking group and R_(a) and R_(b) areindependently aliphatic or aryl, with an organometallic reagent offormula R_(c) M wherein R_(c) is an aliphatic or aryl anion and M is ametal cation; and (b) liberating the ketone compound from the resin. 2.The process of claim 1 wherein M is Li or MgX wherein X is Br or Cl. 3.The process of claim 2 wherein L is a linking group.
 4. The process ofclaim 3 wherein L is a linking group of formula ##STR118## wherein A isabsent or a group of formula --X¹ --Z-- whereinX¹ is --CHR-- or--CH--Y--CO--(CH₂)_(n) -- wherein R is H, alkyl, phenyl, or phenylsubstituted with --H, alkyl, alkoxy, halogen, nitrile or --NO₂, Y is--O-- or --NH--, n is an integer from 1 to 6, and Z is --O-- or --NH--;R¹, R^(1a), R², and R^(2a) are independently --H, alkyl, alkoxy,halogen, nitrile or --NO₂ ; and R³ and R⁴ are independently --H, alkyl,phenyl, or phenyl substituted with one or more substituents selectedfrom alkyl, alkoxy, halogen nitrile and --NO₂ ; or one of R¹ and R²taken together with one of R³ and R⁴ and the carbon atoms to which theyare attached define a linking group of formula ##STR119## wherein R¹ 'is --H, alkyl, alkoxy, halogen, nitrile or --NO₂ ; and R⁶, R⁷ and R⁸ areindependently selected from --H, alkyl, alkoxy, halogen, nitrile or--NO₂.
 5. The process of claim 4 wherein L is a group of formula##STR120## wherein R¹ and R² are independently H or F;R^(1a) and R^(2a)are simultaneously H or F; and one of R³ and R⁴ is H and the other is Hor 2,4-dimethoxyphenyl.
 6. The process of claim 5 wherein R_(b) isalkyl, benzyl or substituted benzyl.
 7. A process for the preparation ofan aldehyde compound of formula R_(a) CHO wherein R_(a) is aliphatic oraryl,comprising (a) reacting an N-alkylated polymeric hydroxamic acidresin compound of formula ##STR121## wherein is a solid support, L isabsent or a linking group and R_(a) and R_(b) are independentlyaliphatic or aryl; with a reducing agent; and (b) liberating thealdehyde compound from the resin.
 8. The process of claim 7 wherein thereducing agent is a hydride reducing agent.
 9. The process of claim 8wherein L is a linking group.
 10. The process of claim 9 wherein L is alinking group of formula ##STR122## wherein A is absent or a group offormula --X¹ --Z-- wherein X¹ is --CHR-- or --CHR--Y--CO--(CH₂)_(n) --wherein R is H, alkyl, phenyl, or phenyl substituted with --H, alkyl,alkoxy, halogen, nitrile or --NO₂,Y is --O-- or --N--, n is an integerfrom 1 to 6, and Z is --O-- or --NH--; R¹, R^(1a), R², and R^(2a) areindependently --H, alkyl, alkoxy, halogen, nitrile or --NO₂ ; and R³ andR⁴ are independently --H, alkyl, phenyl, or phenyl substituted with oneor more substituents selected from alkyl, alkoxy, halogen nitrile and--NO₂ ; or one of R¹ and R² taken together with one of R³ and R⁴ and thecarbon atoms to which they are attached define a linking group offormula ##STR123## wherein R¹ is --H, alkyl, alkoxy, halogen, nitrile or--NO₂ ; and R⁶, R⁷ and R⁸ are independently selected from --H, alkyl,alkoxy, halogen, nitrile or --NO₂.
 11. The process of claim 10 wherein Lis a group of formula ##STR124## wherein R¹ and R² are independently Hor F;R^(1a) and R^(2a) are simultaneously H or F; and one of R³ and R⁴is H and the other is H or 2,4-dimethoxyphenyl.
 12. The process of claim11 wherein R_(b) is alkyl, benzyl or substituted benzyl.
 13. A processfor the preparation of a N-alkylated polymeric hydroxamic acid resincompound of formula ##STR125## wherein is a solid support, L is absentor a linking group and R_(a) and R_(b) are independently aliphatic oraryl;comprising (a) coupling a carboxylic acid compound of formula R_(a)CO₂ H with a polymeric hydroxylamine resin compound of formula##STR126## to form a polymeric hydroxamic acid resin compound of formula##STR127## (b) reacting the polymeric hydroxamic acid resin compoundwith an alkylating agent of formula R_(b) LG wherein LG is a leavinggroup.
 14. The process of claim 13 wherein L is a linking group.
 15. Theprocess of claim 14 wherein L is a linking group of formula ##STR128##wherein A is absent or a group of formula --X¹ --Z-- whereinX¹ is--CHR-- or --CHR--Y--CO--(CH₂)_(n) -- wherein R is H, alkyl, phenyl, orphenyl substituted with --H, alkyl, alkoxy, halogen, nitrile or --NO₂, Yis --O-- or --NH--, n is an integer from 1 to 6, and Z is --O-- or--NH--; R¹, R^(1a), R², and R^(2a) are independently --H, alkyl, alkoxy,halogen, nitrile or --NO₂ ; and R³ and R⁴ are independently --H, alkyl,phenyl, or phenyl substituted with one or more substituents selectedfrom alkyl, alkoxy, halogen nitrile and --NO₂ ; or one of R¹ and R²taken together with one of R³ and R⁴ and the carbon atoms to which theyare attached define a linking group of formula ##STR129## wherein R¹ 'is --H, alkyl, alkoxy, halogen, nitrile or --NO₂ ; and R⁶, R⁷ and R⁸ areindependently selected from --H, alkyl, alkoxy, halogen, nitrile or--NO₂.
 16. The process of claim 15 wherein L is a group of formula##STR130## wherein R¹ and R² are independently H or F;R^(1a) and R^(2a)are simultaneously H or F; and one of R³ and R⁴ is H and the other is Hor 2,4-dimethoxyphenyl.
 17. The process of claim 16 wherein R_(b) isalkyl, benzyl or substituted benzyl.
 18. The process of claim 15 whereinthe polymeric hydroxylamine resin compoundis4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene)resin,4-[4-(-methylhydroxylamine)-3-methoxyphenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%-divinylbenzene)-resin,4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin,4-[4-(1-aminoxyethyl)-2-methoxy-5-nitrophenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%divinylbenzene) resin,O-hydroxylamine-2'-chlorotrityl-copolystyrene-1%-divinylbenzene-resin,O-hydroxylamine-trityl-copolystyrene-1%-divinylbenzene-resin,5-(4-O-methylhydroxylamine -3,5-dimethoxyphenoxy)-valericacid-copolystyrene-1%-divinyl benzene resin,4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin,4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene)resin,4-O-methylhydroxylamine-3-methoxyphenoxy-copolystyrene-1%-divinylbenzeneresin, or 3-hydroxy-xanthydrolamine-copolystryene-1%-divinylbenzeneresin.
 19. The process of claim 16 wherein the polymeric hydroxylamineresin compoundis4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene)resin, or4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin.
 20. A process for the preparation of aN-alkylated polymeric hydroxamic acid resin compound of formula##STR131## wherein is a solid support, L is absent or a linking groupand R_(a) and R_(b) are independently aliphatic or aryl;comprising (a)reacting a N-protected polymeric hydroxamic acid resin compound offormula ##STR132## wherein P is an amine protecting group, with analkylating agent of formula R_(b) LG wherein LG is a leaving group, toform a polymeric N-protected N-alkylated hydroxylamine resin compound offormula ##STR133## (b) removing the amine protecting group to form apolymeric N-alkylated hydroxylamine resin compound of formula ##STR134##(c) coupling the polymeric N-alkylated hydroxylamine resin compound witha carboxylic acid compound of formula R_(a) CO₂ H.
 21. The of claim 20wherein L is a linking group.
 22. The process of claim 21 wherein L is alinking group of formula ##STR135## wherein A is absent or a group offormula --X¹ --Z-- whereinX¹ is --CHR-- or --CHR--Y--CO--(CH₂)_(n) --wherein R is H, alkyl, phenyl, or phenyl substituted with --H, alkyl,alkoxy, halogen, nitrile or --NO₂,Y is --O-- or --NH--, n is an integerfrom 1 to 6, and Z is --O-- or --NH--; R¹, R^(1a), R², and R^(2a) areindependently --H, alkyl, alkoxy, halogen, nitrile or --NO₂ ; and R³ andR⁴ are independently --H, alkyl, phenyl, or phenyl substituted with oneor more substituents selected from alkyl, alkoxy, halogen nitrile and-NO₂ ; or one of R¹ and R² taken together with one of R³ and R⁴ and thecarbon atoms to which they are attached define a linking group offormula ##STR136## wherein R¹ ' is --H, alkyl, alkoxy, halogen, nitrileor --NO₂ ; and R⁶, R⁷ and R⁸ are independently selected from --H, alkyl,alkoxy, halogen, nitrile or --NO₂.
 23. The process of claim 22 wherein Lis a group of formula ##STR137## wherein R¹ and R² are independently Hor F;R^(1a) and R^(2a) are simultaneously H or F; and one of R³ and R⁴is H and the other is H or 2,4-dimethoxyphenyl.
 24. The process of claim23 wherein R_(b) is alkyl, benzyl or substituted benzyl.
 25. The processof claim 24 wherein P is allyloxycarbonyl, benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,trimethylsilylethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, o-nitrobenzylsulfonyl, p-nitrobenzylsulfonyl,and 2-nitro-4-trifluoromethylbenzenesulfonyl.
 26. The process of claim25 wherein P is allyloxycarbonyl.
 27. A polymeric N-protectedhydroxylamine resin compound of formula ##STR138## wherein is a solidsupport;L is absent or a linking group; and P is an amine protectinggroup, provided that P is other than 4-methoxybenzyl or2,4-dimethoxybenzyl.
 28. A polymeric N-protected hydroxylamine resincompound according to claim 27 wherein L is a linking group.
 29. Apolymeric N-protected hydroxylamine resin compound according to claim 28wherein L is a linking group of formula ##STR139## wherein A is absentor a group of formula --X¹ --Z-- whereinX¹ is --CHR-- or--CHR--Y--CO--(CH₂)_(n) -- wherein R is H, alkyl, phenyl, or phenylsubstituted with --H, alkyl, alkoxy, halogen, nitrile or --NO₂, Y is--O-- or --NH--, n is an integer from 1 to 6, and Z is --O-- or --NH--;R¹, R^(1a), R², and R^(2a) are independently --H, alkyl, alkoxy,halogen, nitrile or --NO₂ ; and R³ and R⁴ are independently --H, alkyl,phenyl, or phenyl substituted with one or more substituents selectedfrom alkyl, alkoxy, halogen nitrile and --NO₂ ; or one of R¹ and R²taken together with one of R³ and R⁴ and the carbon atoms to which theyare attached define a linking group of formula ##STR140## wherein R¹ is--H, alkyl, alkoxy, halogen, nitrile or --NO₂ ; and R⁶, R⁷ and R⁸ areindependently selected from --H, alkyl, alkoxy, halogen, nitrile or--NO₂.
 30. A polymeric N-protected hydroxylamine resin compoundaccording to claim 29 wherein L is a group of formula ##STR141## whereinR¹ and R² are independently H or F;R^(1a) and R^(2a) are simultaneouslyH or F; and one of R³ and R⁴ is H and the other is H or2,4-dimethoxyphenyl.
 31. A polymeric N-protected hydroxylamine resincompound according to claim 30 wherein P is allyloxycarbonyl,benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,trimethylsilylethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, o-nitrobenzylsulfonyl, p-nitrobenzylsulfonyl,and 2-nitro-4-trifluoromethylbenzenesulfonyl.
 32. A polymericN-protected hydroxylamine resin compound according to claim 31 wherein Pis allyloxycarbonyl.
 33. A polymeric N-protected hydroxylamine resincompound according to claim 29 which isN-allyloxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene)resin,N-allyloxycarbonyl-4-[4-(O-methylhydroxylamine)-3-methoxyphenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%-divinylbenzene)-resin,N-allyloxycarbonyl-4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%divinylbenzene) resin,N-allyloxycarbonyl-4-[4-(1-aminoxyethyl)-2-methoxy-5-nitrophenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%divinylbenzene) resin,N-allyloxycarbonyl-O-hydroxylamine-2'-chlorotrityl-copolystyrene-1%-divinylbenzene-resin,N-allyloxycarbonyl-O-hydroxylamine-trityl-copolystyrene-1%-divinylbenzene-resin,N-allyloxycarbonyl-5-(4-O-methylhydroxylamine-3,5-dimethoxyphenoxy)-valericacid-copolystyrene-1%-divinyl benzene resin,N-allyloxycarbonyl-4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene) resin,N-allyloxycarbonyl-4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%divinylbenzene)resin,N-allyloxycarbonyl-4-O-methylhydroxylamine-3-methoxyphenoxy-copolystyrene-1%-divinylbenzene resin, orN-allyloxycarbonyl-3-hydroxy-xanthydrolamine-copolystryene-1%-divinylbenzeneresin.
 34. A polymeric N-protected hydroxylamine resin compoundaccording to claim 32 whichisN-allyloxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1%divinylbenzene) resin.
 35. The process of claim 12 wherein R_(a) is theresidual, non-carboxyl portion of a natural or unnatural amino acid orpeptide.
 36. The process of claim 35 wherein the N-terminal nitrogen ofthe natural or unnatural amino acid or peptide is protected with anamine protecting group.
 37. The process of claim 36 wherein the amineprotecting group is tert-butyloxycarbonyl.
 38. A polymeric N-protectedhydroxylamine resin according to claim 29 wherein A is absent and R¹,R^(1a), R², R^(2a), R³ and R⁴ are all hydrogen.
 39. A polymericN-protected hydroxylamine resin according to claim 38 wherein said solidsupport is a Wang resin.
 40. A polymeric N-protected hydroxylamine resinaccording to claim 38 wherein said solid support is a Merrifield resin.41. A polymeric N-protected hydroxylamine resin according to claim 38wherein said solid support comprises a controlled pore glass or amacroporous organic polymer support.
 42. A polymeric N-protectedhydroxylamine resin according to claim 41 wherein said solid support isa macroporous organic polymer support comprising polystyrene.
 43. Apolymeric N-protected hydroxylamine resin according to claim 42 whereinsaid polystyrene is a macroporous styrene-divinyl benzene copolymer. 44.A polymeric N-protected hydroxylamine resin according to claim 38wherein said solid support comprises a polymeric hydroxy resin compoundor a polymeric chloromethyl resin compound.